Alkyl derivatives of 1-oxa-4,9-diazaspiro undecane compounds having multimodal activity against pain

ABSTRACT

The present invention relates to compounds having dual pharmacological activity towards both the sigma (σ) receptor, and the μ-opioid receptor and more particularly to diazaspiro undecane compounds having this pharmacological activity, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy, in particular for the treatment of pain.

FIELD OF THE INVENTION

The present invention relates to compounds having dual pharmacologicalactivity towards both the sigma (σ) receptor, and the μ-opioid receptor(MOR or mu-opioid) and more particularly to diazaspiro undecanederivatives compounds having this pharmacological activity, to processesof preparation of such compounds, to pharmaceutical compositionscomprising them, and to their use in therapy, in particular for thetreatment of pain.

BACKGROUND OF THE INVENTION

The adequate management of pain constitutes an important challenge,since currently available treatments provide in many cases only modestimprovements, leaving many patients unrelieved [Turk D C, Wilson H D,Cahana A. Treatment of chronic non-cancer pain. Lancet 377, 2226-2235(2011)]. Pain affects a big portion of the population with an estimatedprevalence of around 20% and its incidence, particularly in the case ofchronic pain, is increasing due to the population ageing. Additionally,pain is clearly related to comorbidities, such as depression, anxietyand insomnia, which lead to important productivity losses andsocio-economical burden [Goldberg D S, McGee S J. Pain as a globalpublic health priority. BMC Public Health. 11, 770 (2011)]. Existingpain therapies include non-steroidal anti-inflammatory drugs (NSAIDs),opioid agonists, calcium channel blockers and antidepressants, but theyare much less than optimal regarding their safety ratio. All of themshow limited efficacy and a range of secondary effects that precludetheir use, especially in chronic settings.

As mentioned before, there are few available therapeutic classes for thetreatment of pain, and opioids are among the most effective, especiallywhen addressing severe pain states. They act through three differenttypes of opioid receptors (mu, kappa and gamma) which are transmembraneG-protein coupled receptors (GPCRs). Still, the main analgesic action isattributed to the activation of the μ-opioid receptor (MOR). However,the general administration of MOR agonists is limited due to theirimportant side effects, such as constipation, respiratory depression,tolerance, emesis and physical dependence [Meldrum, M. L. (Ed.). Opioidsand Pain Relief: A Historical Perspective. Progress in Pain Research andManagement, Vol 25. IASP Press, Seattle, 2003]. Additionally, MORagonists are not optimal for the treatment of chronic pain as indicatedby the diminished effectiveness of morphine against chronic painconditions. This is especially proven for the chronic pain conditions ofneuropathic or inflammatory origin, in comparison to its high potencyagainst acute pain. The finding that chronic pain can lead to MORdown-regulation may offer a molecular basis for the relative lack ofefficacy of morphine in long-term treatment settings [Dickenson, A. H.,Suzuki, R. Opioids in neuropathic pain: Clues from animal studies. Eur JPain 9, 113-6 (2005)]. Moreover, prolonged treatment with morphine mayresult in tolerance to its analgesic effects, most likely due totreatment-induced MOR down-regulation, internalization and otherregulatory mechanisms. As a consequence, long-term treatment can resultin substantial increases in dosing in order to maintain a clinicallysatisfactory pain relief, but the narrow therapeutic window of MORagonists finally results in unacceptable side effects and poor patientcompliance.

The sigma-1 (σ₁) receptor was discovered 35 years ago and initiallyassigned to a new subtype of the opioid family, but later on and basedon the studies of the enantiomers of SKF-10,047, its independent naturewas established. The first link of the σ₁ receptor to analgesia wasestablished by Chien and Pasternak [Chien C C, Pasternak G W. Sigmaantagonists potentiate opioid analgesia in rats. Neurosci. Lett. 190,137-9 (1995)], who described it as an endogenous anti-opioid system,based on the finding that σ₁ receptor agonists counteracted opioidreceptor mediated analgesia, while σ₁ receptor antagonists, such ashaloperidol, potentiated it.

Many additional preclinical evidences have indicated a clear role of theσ₁ receptor in the treatment of pain [Zamanillo D, Romero L, Merlos M,Vela J M. Sigma 1 receptor: A new therapeutic target for pain. Eur. J.Pharmacol, 716, 78-93 (2013)]. The development of the σ₁ receptorknockout mice, which show no obvious phenotype and perceive normallysensory stimuli, was a key milestone in this endeavour. In physiologicalconditions the responses of the σ₁ receptor knockout mice to mechanicaland thermal stimuli were found to be undistinguishable from WT ones butthey were shown to possess a much higher resistance to develop painbehaviours than WT mice when hypersensitivity entered into play. Hence,in the σ₁ receptor knockout mice capsaicin did not induce mechanicalhypersensitivity, both phases of formalin-induced pain were reduced, andcold and mechanical hypersensitivity were strongly attenuated afterpartial sciatic nerve ligation or after treatment with paclitaxel, whichare models of neuropathic pain. Many of these actions were confirmed bythe use of σ₁ receptor antagonists and led to the advancement of onecompound, S1RA, into clinical trials for the treatment of different painstates. Compound S1RA exerted a substantial reduction of neuropathicpain and anhedonic state following nerve injury (i.e., neuropathic painconditions) and, as demonstrated in an operant self-administrationmodel, the nerve-injured mice, but not sham-operated mice, acquired theoperant responding to obtain it (presumably to get pain relief),indicating that σ₁ receptor antagonism relieves neuropathic pain andalso address some of the comorbidities (i.e., anhedonia, a core symptomin depression) related to pain states.

Pain is multimodal in nature, since in nearly all pain states severalmediators, signaling pathways and molecular mechanisms are implicated.Consequently, monomodal therapies fail to provide complete pain relief.Currently, combining existing therapies is a common clinical practiceand many efforts are directed to assess the best combination ofavailable drugs in clinical studies [Mao J, Gold M S, Backonja M.Combination drug therapy for chronic pain: a call for more clinicalstudies. J. Pain 12, 157-166 (2011)]. Hence, there is an urgent need forinnovative therapeutics to address this unmet medical need.

As mentioned previously, opioids are among the most potent analgesicsbut they are also responsible for various adverse effects whichseriously limit their use.

Accordingly, there is still a need to find compounds that have analternative or improved pharmacological activity in the treatment ofpain, being both effective and showing the desired selectivity, andhaving good “drugability” properties, i.e. good pharmaceuticalproperties related to administration, distribution, metabolism andexcretion.

Thus, the technical problem can therefore be formulated as findingcompounds that have an alternative or improved pharmacological activityin the treatment of pain.

In view of the existing results of the currently available therapies andclinical practices, the present invention offers a solution by combiningin a single compound binding to two different receptors relevant for thetreatment of pain. This was mainly achieved by providing the compoundsaccording to the invention that bind both to the μ-opioid receptor andto the σ₁ receptor.

SUMMARY OF THE INVENTION

In this invention a family of structurally distinct diazaspiro undecanederivatives which have a dual pharmacological activity towards both thesigma (σ) receptor, and the μ-opioid receptor was identified thussolving the above problem of identifying alternative or improved paintreatments by offering such dual compounds.

The invention is in one aspect directed to a compound having a dualactivity binding to the σ₁ receptor and the μ-opioid receptor for use inthe treatment of pain.

As this invention is aimed at providing a compound or a chemicallyrelated series of compounds which act as dual ligands of the σ₁ receptorand the μ-opioid receptor it is a very preferred embodiment if thecompound has a binding expressed as K_(i) which is preferably <1000 nMfor both receptors, more preferably <500 nM, even more preferably <100nM.

The invention is directed in a main aspect to a compound of generalformula (I),

wherein R₁, R₂, R₃, R_(3′) are as defined below in the detaileddescription.

DETAILED DESCRIPTION OF THE INVENTION

The invention is directed to a family of structurally distinctdiazaspiro undecane derivatives which have a dual pharmacologicalactivity towards both the sigma (σ) receptor, and the μ-opioid receptorwas identified thus solving the above problem of identifying alternativeor improved pain treatments by offering such dual compounds.

The invention is in one aspect directed to a compound having a dualactivity binding to the σ₁ receptor and the μ-opioid receptor for use inthe treatment of pain.

As this invention is aimed at providing a compound or a chemicallyrelated series of compounds which act as dual ligands of the σ₁ receptorand the μ-opioid receptor it is a very preferred embodiment if thecompound has a binding expressed as Ki which is preferably <1000 nM forboth receptors, more preferably <500 nM, even more preferably <100 nM.

The applicant has surprisingly found that the problem on which thepresent invention is based can be solved by using a multimodal balancedanalgesic approach combining two different synergistic activities in asingle drug (i.e., dual ligands which are bifunctional and bind to MORand to σ₁ receptor), thereby enhancing the opioid analgesia through theσ₁ activation without increasing the undesirable side effects.

This supports the therapeutic value of a dual MOR/σ₁ receptor compoundwhereby the σ₁ receptor binding component acts as an intrinsic adjuvantof the MOR binding component.

This solution offered the advantage that the two mechanisms complementeach other in order to treat pain and chronic pain using lower andbetter tolerated doses needed based on the potentiation of analgesia butavoiding the adverse events of μ opioid receptor agonists.

A dual compound that possess binding to both the μ-opioid receptor andto the σ₁ receptor shows a highly valuable therapeutic potential byachieving an outstanding analgesia (enhanced in respect to the potencyof the opioid component alone) with a reduced side-effect profile(safety margin increased compared to that of the opioid component alone)versus existing opioid therapies.

Advantageously, the dual compounds according to the present inventionwould in addition show one or more the following functionalities: σ₁receptor antagonism and MOR agonism. It has to be noted, though, thatboth functionalities “antagonism” and “agonism” are also sub-divided intheir effect into subfunctionalities like partial agonism or inverseagonism. Accordingly, the functionalities of the dual compound should beconsidered within a relatively broad bandwidth.

An antagonist on one of the named receptors blocks or dampensagonist-mediated responses. Known subfunctionalities are neutralantagonists or inverse agonists.

An agonist on one of the named receptors increases the activity of thereceptor above its basal level. Known subfunctionalities are fullagonists, or partial agonists.

In addition, the two mechanisms complement each other since MOR agonistsare only marginally effective in the treatment of neuropathic pain,while σ₁ receptor antagonists show outstanding effects in preclinicalneuropathic pain models. Thus, the σ₁ receptor component adds uniqueanalgesic actions in opioid-resistant pain. Finally, the dual approachhas clear advantages over MOR agonists in the treatment of chronic painas lower and better tolerated doses would be needed based on thepotentiation of analgesia but not of the adverse events of MOR agonists.

A further advantage of using designed multiple ligands is a lower riskof drug-drug interactions compared to cocktails or multi-componentdrugs, thus involving simpler pharmacokinetics and less variabilityamong patients. Additionally, this approach may improve patientcompliance and broaden the therapeutic application in relation tomonomechanistic drugs, by addressing more complex aetiologies. It isalso seen as a way of improving the R&D output obtained using the “onedrug-one target” approach, which has been questioned over the last years[Bornot A, Bauer U, Brown A, Firth M, Hellawell C, Engkvist O.Systematic Exploration of Dual-Acting Modulators from a CombinedMedicinal Chemistry and Biology Perspective. J. Med. Chem, 56, 1197-1210(2013)].

It has also surprisingly been found that the affinity for the μ-opioidreceptor of the 1-oxa-4,9-diazaspiro[5.5]undecane derivatives describedherein depends heavily on the precise nature of the substituents in R₃position of Formula (I) and on their particular spatial configuration.

The binding affinity for the μ-opioid receptor was surprisingly found toreside predominantly in the R₃ substituent (different from hydrogen)occupying the spatial configuration as shown in Formula (I),independently of R₃ and R_(3′) being the same substituents, differentsubstituents (leading to a chiral center) or forming a cycloalkyl group.While when R₃ is hydrogen, the binding to the μ-opioid receptor is muchweaker.

The affinity for the σ₁ receptor was basically maintained, beinginfluenced in a lesser extent by the spatial configuration of theradicals in position R₃ or R_(3′).

The optical isomers have been obtained by convenient enantioselectivemethods or via chiral HPLC separation or fractional crystallization ofdiastereomeric salts of the corresponding racemic mixtures.

In a particular aspect, the present invention is directed to compoundsof general formula (I):

whereinR₁ is substituted or unsubstituted C₁₋₆ alkyl, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₃₋₆ cycloalkyl, substituted orunsubstituted C₄₋₇ alkylcycloalkyl;R₂ is substituted or unsubstituted monocyclic aryl or substituted orunsubstituted monocyclic heterocyclylR₃ is substituted or unsubstituted C₁₋₆ alkyl, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₃₋₆ cycloalkyl, substituted orunsubstituted C₄₋₇ alkylcycloalkyl, substituted or unsubstituted C₄₋₇alkylaryl, substituted or unsubstituted C₃₋₆ aryl, substituted orunsubstituted C₃₋₆ heterocyclyl or substituted or unsubstituted C₄₋₇alkylheterocyclyl;R_(3′) is hydrogen or unsubstituted C₁₋₆ alkyl, unsubstituted C₂₋₆alkenyl or unsubstituted C₂₋₆ alkynyl,alternatively R₃ and R_(3′) taken together (with the connecting C-atom)may form an substituted or unsubstituted C₃₋₆ cycloalkyl;R₄, R_(4′) and R_(4″) are independently selected from hydrogen orsubstituted or unsubstituted C₁₋₆ alkyl, substituted or unsubstitutedC₂₋₆ alkenyl or substituted or unsubstituted C₂₋₆ alkynyl, substitutedor unsubstituted C₃₋₆ cycloalkyl;R_(4″′) is hydrogen or unsubstituted C₁₋₆ alkyl, unsubstituted C₂₋₆alkenyl, unsubstituted C₂₋₆ alkynyl or -Boc;optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof, or a correspondingsolvate thereof.

Please note that “or a corresponding salt thereof” does also mean “or acorresponding pharmaceutically acceptable salt thereof”. This does applyto all below described embodiments and uses of “salt” being thusequivalent to “pharmaceutically acceptable salt”.

In a particular embodiment one or more of the following compounds areexcluded:

-   2,4-dimethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,    and/or-   2-ethyl-4-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,    and/or-   2-isopropyl-4-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,    and/or-   2-butyl-4-ethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one

-   -   In a particular embodiment this exclusion only refers to the        respective racemic form of this or these compound/s above.    -   In a particular embodiment all these 4 compounds above are        excluded.    -   In a particular embodiment this exclusion also includes all the        HCl salts of these compounds above or their pharmaceutically        acceptable acid addition salts.

Some compounds from the state of the art (U.S. Pat. No. 4,353,900A) havebeen identified which are not part of the present invention since, asracemic compounds, they lack information on the spatial conformation ofthe group corresponding to R₃ in Formula (I). These compounds respond tothe following names and formulae:

-   2,4-dimethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one-   2-ethyl-4-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one-   2-isopropyl-4-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one-   2-butyl-4-ethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one

In another particular embodiment the condition/proviso appliesespecially for a compound according to Formula I that if R₂ isunsubstituted phenyl, R_(3′) is hydrogen and R₃ is C₁₋₄-alkyl, then R₁may not be C₁₋₂-alkyl.

In the context of this invention, alkyl is understood as meaningsaturated, linear or branched hydrocarbons, which may be unsubstitutedor substituted once or several times. It encompasses e.g. —CH₃ and—CH₂—CH₃. In these radicals, C₁₋₂-alkyl represents C1- or C2-alkyl,C₁₋₃-alkyl represents C1-, C2- or C3-alkyl, C₁₋₄-alkyl represents C1-,C2-, C3- or C4-alkyl, C₁₋₅-alkyl represents C1-, C2-, C3-, C4-, orC5-alkyl, C₁₋₆-alkyl represents C1-, C2-, C3-, C4-, C5- or C6-alkyl,C₁₋₇-alkyl represents C1-, C2-, C3-, C4-, C5-, C6- or C7-alkyl,C₁₋₈-alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7- or C8-alkyl,C₁₋₁₀-alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9- orC10-alkyl and C₁₋₁₈-alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7-,C8-, C9-, C10-, C11-, C12-, C13-, C14-, C15-, C16-, C17- or C18-alkyl.The alkyl radicals are preferably methyl, ethyl, propyl, methylethyl,butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl,1-methylpentyl, if substituted also CHF₂, CF₃ or CH₂OH etc. Preferablyalkyl is understood in the context of this invention as C₁₋₈alkyl likemethyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl;preferably is C₁₋₆alkyl like methyl, ethyl, propyl, butyl, pentyl, orhexyl; more preferably is C₁₋₄alkyl like methyl, ethyl, propyl or butyl.

Alkenyl is understood as meaning unsaturated, linear or branchedhydrocarbons, which may be unsubstituted or substituted once or severaltimes. It encompasses groups like e.g. —CH═CH—CH₃. The alkenyl radicalsare preferably vinyl (ethenyl), allyl (2-propenyl). Preferably in thecontext of this invention alkenyl is C₂₋₁₀-alkenyl or C₂₋₈-alkenyl likeethylene, propylene, butylene, pentylene, hexylene, heptylene oroctylene; or is C₂₋₆-alkenyl like ethylene, propylene, butylene,pentylene, or hexylene; or is C₂₋₄-alkenyl, like ethylene, propylene, orbutylenes.

Alkynyl is understood as meaning unsaturated, linear or branchedhydrocarbons, which may be unsubstituted or substituted once or severaltimes. It encompasses groups like e.g. —C═C—CH₃ (1-propinyl). Preferablyalkynyl in the context of this invention is C₂₋₁₀-alkynyl orC₂₋₈-alkynyl like ethyne, propyne, butyene, pentyne, hexyne, heptyne, oroctyne; or is C₂₋₆-alkynyl like ethyne, propyne, butyene, pentyne, orhexyne; or is C₂₋₄-alkynyl like ethyne, propyne, butyene, pentyne, orhexyne.

In the context of this invention cycloalkyl is understood as meaningsaturated and unsaturated (but not aromatic) cyclic hydrocarbons(without a heteroatom in the ring), which can be unsubstituted or onceor several times substituted. Furthermore, C₃₋₄₋cycloalkyl representsC3- or C4-cycloalkyl, C₃₋₅-cycloalkyl represents C3-, C4- orC5-cycloalkyl, C₃₋₆-cycloalkyl represents C3-, C4-, C5- orC6-cycloalkyl, C₃₋₇-cycloalkyl represents C3-, C4-, C5-, C6- orC7-cycloalkyl, C₃₋₈-cycloalkyl represents C3-, C4-, C5-, C6-, C7- orC8-cycloalkyl, C₄₋₅-cycloalkyl represents C4- or C5-cycloalkyl,C₄₋₆-cycloalkyl represents C4-, C5- or C6-cycloalkyl, C₄₋₇-cycloalkylrepresents C4-, C5-, C6- or C7-cycloalkyl, C₅₋₆-cycloalkyl representsC5- or C6-cycloalkyl and C₅₋₇-cycloalkyl represents C5-, C6- orC7-cycloalkyl. Examples are cyclopropyl, 2-methylcyclopropyl,cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylmethyl,cyclohexyl, cycloheptyl, cyclooctyl, and also adamantly. Preferably inthe context of this invention cycloalkyl is C₃₋₈cycloalkyl likecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, orcyclooctyl; or is C₃₋₇cycloalkyl like cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, or cycloheptyl; or is C₃₋₆cycloalkyl likecyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, especiallycyclopentyl or cyclohexyl.

In connection with alkyl, alkenyl, alkynyl and O-alkyl—unless definedotherwise—the term substituted in the context of this invention isunderstood as meaning replacement of at least one hydrogen radical on acarbon atom by halogen (F, Cl, I, Br), NR₄R_(4″′), SR₄, —S(O)R₄,—S(O)₂R₄, —OR₄, —C(O)OR₄, —CN, haloalkyl, haloalkoxy or —OC₁₋₄alkylbeing unsubstituted or substituted by one or more of OH or halogen (F,Cl, I, Br), being R₄, R_(4′), R_(4″) and R_(4″′) as defined above, andwherein when different radicals R₁ to R_(4″″) are present simultaneouslyin Formulas I to I″ they may be identical or different. More than onereplacement on the same molecule and also on the same carbon atom ispossible with the same or different substituents. This includes forexample 3 hydrogens being replaced on the same C atom, as in the case ofCF₃, or at different places of the same molecule, as in the case of e.g.—CH(OH)—CH═CH—CHCl₂, when different radicals R₁ to R_(4″″) are presentsimultaneously in Formulas I to I″ they may be identical or different.

Preferably in connection with alkyl, alkenyl, alkynyl or O-alkyl,substituted is understood in the context of this invention that anyalky, alkenyl, alkynyl or O-alkyl which is substituted is substituted byone or more of halogen (F, Cl, I, Br), —OR₄, —CN, haloalkyl, or—OC₁₋₄alkyl being unsubstituted or substituted by one or more of OH orhalogen (F, Cl, I, Br), being R₄, R_(4′), R_(4″) and R_(4″′) as definedabove, and wherein when different radicals R₁ to R_(4″″) are presentsimultaneously in Formulas I to I″ they may be identical or different.

Preferably in connection with alkyl, alkenyl, alkynyl or O-alkyl,substituted is understood in the context of this invention that anyalky, alkenyl, alkynyl or O-alkyl which is substituted is substituted byone or more of halogen (F, Cl, I, Br), —OR₄, —CN, or haloalkyl, beingR₄, R_(4′), R_(4″) and R_(4″′) as defined above, and wherein whendifferent radicals R₁ to R_(4″″) are present simultaneously in FormulasI to I″ they may be identical or different.

Most preferably in connection with alkyl, alkenyl, alkynyl or O-alkyl,substituted is understood in the context of this invention that anyalky, alkenyl, alkynyl or O-alkyl which is substituted is substituted byone or more of halogen (F, Cl, I, Br), —CN, or haloalkyl.

More than one replacement on the same molecule and also on the samecarbon atom is possible with the same or different substituents. Thisincludes for example 3 hydrogens being replaced on the same C atom, asin the case of CF₃, or at different places of the same molecule, as inthe case of e.g. —CH(OH)—CH═CH—CHCl₂.

In the context of this invention haloalkyl is understood as meaning analkyl being substituted once or several times by a halogen (selectedfrom F, Cl, Br, I). It encompasses e.g. —CH₂Cl, —CH₂F, —CHCl₂, —CHF₂,—CCl₃, —CF₃ and —CH₂—CHCl₂. Preferably haloalkyl is understood in thecontext of this invention as halogen-substituted C₁₋₄-alkyl representinghalogen substituted C1-, C2-, C3- or C4-alkyl. The halogen-substitutedalkyl radicals are thus preferably methyl, ethyl, propyl, and butyl.Preferred examples include —CH₂Cl, —CH₂F, —CHCl₂, —CHF₂, and —CF₃.

In the context of this invention haloalkoxy is understood as meaning an—O-alkyl being substituted once or several times by a halogen (selectedfrom F, Cl, Br, I). It encompasses e.g. —OCH₂Cl, —OCH₂F, —OCHCl₂,—OCHF₂, —OCCl₃, —OCF₃ and —OCH₂—CHCl₂. Preferably haloalkyl isunderstood in the context of this invention as halogen-substituted—OC₁₋₄-alkyl representing halogen substituted C1-, C2-, C3- orC4-alkoxy. The halogen-substituted alkyl radicals are thus preferablyO-methyl, O-ethyl, O-propyl, and O-butyl. Preferred examples include—OCH₂Cl, —OCH₂F, —OCHCl₂, —OCHF₂, and —OCF₃.

Aryl is understood as meaning ring systems with at least one aromaticring but without heteroatoms even in only one of the rings. Examples arephenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl or indanyl, inparticular 9H-fluorenyl or anthracenyl radicals, which can beunsubstituted or once or several times substituted. Most preferably arylis understood in the context of this invention as phenyl, naphtyl oranthracenyl, preferably is phenyl.

In the context of this invention alkyl-aryl is understood as meaning anaryl group (see above) being connected to another atom through 1 to 4(—CH₂—) groups. Most preferably alkyl-aryl is benzyl. Thus, e.g. C₄₋₇alkylaryl means that the combined number of C-atoms in the aryl groupand in the 1 to 4 (—CH₂—) groups with which the aryl is being connectedto another atom is between 4 and 7.

In the context of this invention alkylheterocyclyl is understood asmeaning an heterocyclyl group (see underneath) being connected toanother atom through 1 to 4 (—CH₂—) groups. Most preferablyalkylheterocyclyl is —CH₂-pyridine. Thus, e.g. C₄₋₇ alkylheterocyclylmeans that the combined number of C-atoms in the heterocyclyl group andin the 1 to 4 (—CH₂—) groups with which the heterocyclyl is beingconnected to another atom is between 4 and 7.

In the context of this invention alkylcycloalkyl is understood asmeaning an cycloalkyl group (see above) being connected to another atomthrough 1 to 4 (—CH₂—) groups. Most preferably alkylcycloalkyl is—CH₂-cyclopropyl. Thus, e.g. C₄₋₇ alkylcycloalkyl means that thecombined number of C-atoms in the cycloalkyl group and in the 1 to 4(—CH₂—) groups with which the cycloalkyl is being connected to anotheratom is between 4 and 7.

In a more general sense, a heterocyclyl radical or group is understoodas meaning heterocyclic ring systems, with at least one saturated orunsaturated ring which contains one or more heteroatoms from the groupconsisting of nitrogen, oxygen and/or sulfur in the ring. A heterocyclicgroup can also be substituted once or several times. Examples includeheteroaryls such as furan, benzofuran, thiophene, benzothiophene,pyrrole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline,phthalazine, benzo-1,2,5-thiadiazole, benzothiazole, indole,benzotriazole, benzodioxolane, benzodioxane, carbazole and quinazoline.Preferably in the context of this invention heterocyclyl is defined as aheterocyclic ring system of one or more saturated or unsaturated ringsof which at least one ring contains one or more heteroatoms from thegroup consisting of nitrogen, oxygen and/or sulfur in the ring.Preferably it is a heterocyclic ring system of one or two saturated orunsaturated rings of which at least one ring contains one or moreheteroatoms from the group consisting of nitrogen, oxygen and/or sulfurin the ring. Preferred examples include imidazole, oxadiazole,tetrazole, pyridine, pyrimidine, piperidine, piperazine, indene,2,3-dihydroindene, benzofuran, benzimidazole, indazole, benzothiazole,benzodiazole, thiazole, benzothiazole, tetrahydropyrane, morpholine,indoline, furan, triazole, isoxazole, pyrazole, thiophene,benzothiophene, pyrrole, pyrazine, pyrrolo[2,3b]pyridine, quinoline,isoquinoline, phthalazine, benzo-1,2,5-thiadiazole, indole,benzotriazole, benzoxazole oxopyrrolidine, pyrimidine, benzodioxolane,benzodioxane, carbazole and quinazoline, especially is pyridine,pyrazine, indazole, benzodioxane, thiazole, benzothiazole, morpholine,tetrahydropyrane, pyrazole, imidazole, piperidine, pyrazole, thiophene,indole, benzimidazole, pyrrolo[2,3b]pyridine, benzoxazole,oxopyrrolidine, pyrimidine.

In a more specific sense, a heterocyclyl radical or group (also calledheterocyclyl hereinafter) is understood as meaning heterocyclic ringsystems, with at least one saturated or unsaturated ring which containsone or more heteroatoms from the group consisting of nitrogen, oxygenand/or sulfur in the ring. A heterocyclic group can also be substitutedonce or several times.

Examples include non-aromatic heterocyclyls such as tetrahydropyrane,oxazepane, morpholine, piperidine, pyrrolidine as well as heteroarylssuch as furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine,pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine, thiazole,benzothiazole, indole, benzotriazole, carbazole and quinazoline.

Subgroups inside the heterocyclyls as understood herein includeheteroaryls and non-aromatic heterocyclyls.

-   -   the heteroaryl (being equivalent to heteroaromatic radicals or        aromatic heterocyclyls) is an aromatic heterocyclic ring system        of one or more rings of which at least one aromatic ring        contains one or more heteroatoms from the group consisting of        nitrogen, oxygen and/or sulfur in the ring; preferably is an        aromatic heterocyclic ring system of one or two rings of which        at least one aromatic ring contains one or more heteroatoms from        the group consisting of nitrogen, oxygen and/or sulfur in the        ring, more preferably is selected from furan, benzofuran,        thiophene, benzothiophene, pyrrole, pyridine, pyrimidine,        pyrazine, quinoline, isoquinoline, phthalazine, benzothiazole,        indole, benzotriazole, carbazole, quinazoline, thiazole,        imidazole, pyrazole, oxazole, thiophene and benzimidazole;    -   the non-aromatic heterocyclyl is a heterocyclic ring system of        one or more rings of which at least one ring—with this (or        these) ring(s) then not being aromatic—contains one or more        heteroatoms from the group consisting of nitrogen, oxygen and/or        sulfur in the ring; preferably is a heterocyclic ring system of        one or two rings of which one or both rings—with this one or two        rings then not being aromatic—contain/s one or more heteroatoms        from the group consisting of nitrogen, oxygen and/or sulfur in        the ring, more preferably is selected from oxazepam,        pyrrolidine, piperidine, piperazine, tetrahydropyran,        morpholine, indoline, oxopyrrolidine, benzodioxane, especially        is benzodioxane, morpholine, tetrahydropyran, piperidine,        oxopyrrolidine and pyrrolidine.

Preferably in the context of this invention heterocyclyl is defined as aheterocyclic ring system of one or more saturated or unsaturated ringsof which at least one ring contains one or more heteroatoms from thegroup consisting of nitrogen, oxygen and/or sulfur in the ring.Preferably it is a heterocyclic ring system of one or two saturated orunsaturated rings of which at least one ring contains one or moreheteroatoms from the group consisting of nitrogen, oxygen and/or sulfurin the ring.

Preferred examples of heterocyclyls include oxazepane, pyrrolidine,imidazole, oxadiazole, tetrazole, pyridine, pyrimidine, piperidine,piperazine, benzofuran, benzimidazole, indazole, benzodiazole, thiazole,benzothiazole, tetrahydropyrane, morpholine, indoline, furan, triazole,isoxazole, pyrazole, thiophene, benzothiophene, pyrrole, pyrazine,pyrrolo[2,3b]pyridine, quinoline, isoquinoline, phthalazine,benzo-1,2,5-thiadiazole, indole, benzotriazole, benzoxazoleoxopyrrolidine, pyrimidine, benzodioxolane, benzodioxane, carbazole andquinazoline, especially is pyridine, pyrazine, indazole, benzodioxane,thiazole, benzothiazole, morpholine, tetrahydropyrane, pyrazole,imidazole, piperidine, thiophene, indole, benzimidazole,pyrrolo[2,3b]pyridine, benzoxazole, oxopyrrolidine, pyrimidine,oxazepane and pyrrolidine.

In the context of this invention oxopyrrolidine is understood as meaningpyrrolidin-2-one.

In connection with aromatic heterocyclyls (heteroaryls), non-aromaticheterocyclyls, aryls and cycloalkyls, when a ring system falls withintwo or more of the above cycle definitions simultaneously, then the ringsystem is defined first as an aromatic heterocyclyl (heteroaryl) if atleast one aromatic ring contains a heteroatom. If no aromatic ringcontains a heteroatom, then the ring system is defined as a non-aromaticheterocyclyl if at least one non-aromatic ring contains a heteroatom. Ifno non-aromatic ring contains a heteroatom, then the ring system isdefined as an aryl if it contains at least one aryl cycle. If no aryl ispresent, then the ring system is defined as a cycloalkyl if at least onenon-aromatic cyclic hydrocarbon is present.

Preferably, the aryl is a monocyclic aryl.

Preferably, the heteroaryl is a monocyclic heteroaryl.

Preferably, the non-aromatic heterocyclyl is a monocyclic non-aromaticheterocyclyl.

Preferably, the cycloalkyl is a monocyclic cycloalkyl.

In connection with aryl (including alkyl-aryl), cycloalkyl (includingalkyl-cycloalkyl) or heterocyclyl (including alkyl-heterocyclyl),substituted is understood—unless defined otherwise—as meaningsubstitution of the ring-system of the aryl or alkyl-aryl, cycloalkyl oralkyl-cycloalkyl; heterocyclyl or alkyl-heterocyclyl by —R₄, —OR₄,halogen, ═O, —OCH₂CH₂OH, —SR₄, —S(O)R₄, —S(O)₂R₄, —CN,haloalkyl,-haloalkoxy, —NR₄R_(4″′), —NO₂, —NR₄C(O)R₄, —NR₄SO₂R_(4′),—C(O)OR₄, —C(O)NR₄R_(4′), —NR₄C(O)NR_(4′)R_(4″), —S(O)₂NR₄R_(4′),—NR₄S(O)₂NR_(4′)R_(4″); NR_(x)R_(y), with R_(x) and R_(y) independentlybeing either H or a saturated or unsaturated, linear or branched,substituted or unsubstituted C₁₋₆-alkyl; a saturated or unsaturated,linear or branched, substituted or unsubstituted C₁₋₆-alkyl; a saturatedor unsaturated, linear or branched, substituted or unsubstituted—O—C₁₋₆-alkyl (alkoxy); a saturated or unsaturated, linear or branched,substituted or unsubstituted —S—C₁₋₆-alkyl; a saturated or unsaturated,linear or branched, substituted or unsubstituted —C(O)—C₁₋₆—alkyl-group; a saturated or unsaturated, linear or branched, substitutedor unsubstituted —C(O)—O—C₁₋₆— alkyl-group; a substituted orunsubstituted aryl or alkyl-aryl; a substituted or unsubstitutedcycloalkyl or alkyl-cycloalkyl; a substituted or unsubstitutedheterocyclyl or alkyl-heterocyclyl, being R₄, R_(4′), R_(4″), andR_(4″′) as defined above, and wherein when different radicals R₁ toR_(4″″) are present simultaneously in Formulas I to I″ they may beidentical or different.

Preferably in connection with aryl (including alkyl-aryl), cycloalkyl(including alkyl-cycloalkyl) or heterocyclyl (includingalkyl-heterocyclyl), substituted is understood in the context of thisinvention that any aryl, cycloalkyl and heterocyclyl which issubstituted is substituted by one or more of —OR₄, halogen, —CN,haloalkyl-haloalkoxy, —NR₄R_(4″′), —NO₂, —NR₄C(O)R_(4′), —C(O)OR₄,—C(O)NR₄R_(4′), —NR₄C(O)NR_(4′)R_(4″), —S(O)₂NR₄R_(4′), —OC₁₋₄alkylbeing unsubstituted or substituted by one or more of OH or halogen (F,Cl, I, Br), —CN, or —C₁₋₄alkyl being unsubstituted or substituted by oneor more of OH or halogen (F, Cl, I, Br), being R₄, R_(4′), R_(4″) andR_(4″′) as defined above, and wherein when different radicals R₁ toR_(4″″) are present simultaneously in Formulas I to I″ they may beidentical or different.

Most preferably in connection with aryl (including alkyl-aryl),cycloalkyl (including alkyl-cycloalkyl) or heterocyclyl (includingalkyl-heterocyclyl), substituted is understood in the context of thisinvention that any aryl, cycloalkyl and heterocyclyl which issubstituted is substituted by one or more of —OR₄, halogen, —CN,haloalkyl-haloalkoxy, —NR₄R_(4″′), —NO₂, —NR₄C(O)R_(4′), —C(O)NR₄R_(4′),—NR₄C(O)NR_(4′)R_(4″), —S(O)₂NR₄R_(4′), —OC₁₋₄alkyl being unsubstitutedor substituted by one or more of OH or halogen (F, Cl, I, Br), —CN, or—C₁₋₄alkyl being unsubstituted or substituted by one or more of OH orhalogen (F, Cl, I, Br), being R₄, R_(4′), R_(4″) and R_(4″′) as definedabove, and wherein when different radicals R₁ to R_(4″″) are presentsimultaneously in Formulas I to I″ they may be identical or different.

Most preferably in connection with aryl (including alkyl-aryl),cycloalkyl (including alkyl-cycloalkyl) or heterocyclyl (includingalkyl-heterocyclyl), substituted is understood in the context of thisinvention that any aryl, cycloalkyl and heterocyclyl which issubstituted is substituted by one or more of —R_(4″′), —OR_(4″′),halogen, ═O, —OCH₂CH₂OH, —SR_(4″′), —S(O)R_(4″′), —S(O)₂R_(4″′), —CN,haloalkyl-haloalkoxy, —NR_(4″′)R_(4″′), —NO₂, —NR_(4″′)C(O)R_(4″′),—NR_(4″′)SO₂R_(4″′), —C(O)OR_(4″′), —C(O)NR_(4″′)R_(4″′),—NR_(4″′)C(O)NR_(4″′)R_(4″′), —S(O)₂NR_(4″′)R_(4″′),—NR_(4″′)S(O)₂NR_(4″′)R_(4″′), —OC₁₋₄alkyl being unsubstituted orsubstituted by one or more of OH or halogen (F, Cl, I, Br), —CN, or—C₁₋₄alkyl being unsubstituted or substituted by one or more of OH orhalogen (F, Cl, I, Br), being R₄, R_(4′), R_(4″) and R_(4″′) as definedabove, and wherein when different radicals R₁ to R_(4″″) are presentsimultaneously in Formulas I to I″ they may be identical or different.Most preferably in connection with aryl (including alkyl-aryl),cycloalkyl (including alkyl-cycloalkyl) or heterocyclyl (includingalkyl-heterocyclyl), substituted is understood in the context of thisinvention that any aryl, cycloalkyl and heterocyclyl which issubstituted is substituted by one or more of —R_(4″′), halogen,—SR_(4″′), —CN, haloalkyl, —NR_(4″′)R_(4″′), —OC₁₋₄alkyl beingunsubstituted or substituted by one or more of OH or halogen (F, Cl, I,Br), —CN, or —C₁₋₄alkyl being unsubstituted or substituted by one ormore of OH or halogen (F, Cl, I, Br), being R₄, R_(4′), R_(4″) andR_(4″′) as defined above, and wherein when different radicals R₁ toR_(4″″) are present simultaneously in Formulas I to I″ they may beidentical or different.

Most preferably in connection with aryl (including alkyl-aryl),cycloalkyl (including alkyl-cycloalkyl) or heterocyclyl (includingalkyl-heterocyclyl), substituted is understood in the context of thisinvention that any aryl, cycloalkyl and heterocyclyl which issubstituted is substituted by one or more —OR_(4″′), halogen, —CN,haloalkyl, -haloalkoxy, —OC₁₋₄alkyl being unsubstituted or substitutedby one or more of OH or halogen (F, Cl, I, Br), —CN, or —C₁₋₄alkyl beingunsubstituted or substituted by one or more of OH or halogen (F, Cl, I,Br), being R₄, R_(4′), R_(4″) and R_(4″′) as defined above, and whereinwhen different radicals R₁ to R_(4″″) are present simultaneously inFormulas I to I″ they may be identical or different.

Additionally to the above-mentioned substitutions, in connection withcycloalkyl, or heterocycly namely non-aromatic heterocyclyl, substitutedis also understood—unless defined otherwise—as meaning substitution ofthe ring-system of the cycloalkyl or; non-aromatic heterocyclyl with

═O.

The term “leaving group” means a molecular fragment that departs with apair of electrons in heterolytic bond cleavage. Leaving groups can beanions or neutral molecules. Common anionic leaving groups are halidessuch as Cl—, Br—, and I—, and sulfonate esters, such as tosylate (TsO—)or mesylate.

The term “salt” is to be understood as meaning any form of the activecompound used according to the invention in which it assumes an ionicform or is charged and is coupled with a counter-ion (a cation or anion)or is in solution. By this are also to be understood complexes of theactive compound with other molecules and ions, in particular complexesvia ionic interactions.

The term “physiologically acceptable salt” means in the context of thisinvention any salt that is physiologically tolerated (most of the timemeaning not being toxic-especially not caused by the counter-ion) ifused appropriately for a treatment especially if used on or applied tohumans and/or mammals.

These physiologically acceptable salts can be formed with cations orbases and in the context of this invention is understood as meaningsalts of at least one of the compounds used according to theinvention—usually a (deprotonated) acid—as an anion with at least one,preferably inorganic, cation which is physiologicallytolerated—especially if used on humans and/or mammals. The salts of thealkali metals and alkaline earth metals are particularly preferred, andalso those with NH₄, but in particular (mono)- or (di)sodium, (mono)- or(di)potassium, magnesium or calcium salts.

Physiologically acceptable salts can also be formed with anions or acidsand in the context of this invention is understood as meaning salts ofat least one of the compounds used according to the invention as thecation with at least one anion which are physiologicallytolerated—especially if used on humans and/or mammals. By this isunderstood in particular, in the context of this invention, the saltformed with a physiologically tolerated acid, that is to say salts ofthe particular active compound with inorganic or organic acids which arephysiologically tolerated—especially if used on humans and/or mammals.Examples of physiologically tolerated salts of particular acids aresalts of: hydrochloric acid, hydrobromic acid, sulfuric acid,methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinicacid, malic acid, tartaric acid, mandelic acid, fumaric acid, lacticacid or citric acid.

The compounds of the invention may be present in crystalline form or inthe form of free compounds like a free base or acid.

Any compound that is a solvate of a compound according to the inventionlike a compound according to general formula I defined above isunderstood to be also covered by the scope of the invention. Methods ofsolvation are generally known within the art. Suitable solvates arepharmaceutically acceptable solvates. The term “solvate” according tothis invention is to be understood as meaning any form of the activecompound according to the invention in which this compound has attachedto it via non-covalent binding another molecule (most likely a polarsolvent). Especially preferred examples include hydrates andalcoholates, like methanolates or ethanolates.

Any compound that is a prodrug of a compound according to the inventionlike a compound according to general formula I defined above isunderstood to be also covered by the scope of the invention. The term“prodrug” is used in its broadest sense and encompasses thoseDerivatives that are converted in vivo to the compounds of theinvention. Such Derivatives would readily occur to those skilled in theart, and include, depending on the functional groups present in themolecule and without limitation, the following Derivatives of thepresent compounds: esters, amino acid esters, phosphate esters, metalsalts sulfonate esters, carbamates, and amides. Examples of well knownmethods of producing a prodrug of a given acting compound are known tothose skilled in the art and can be found e.g. in Krogsgaard-Larsen etal. “Textbook of Drug design and Discovery” Taylor & Francis (April2002).

Unless otherwise stated, the compounds of the invention are also meantto include compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of an hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbonor of a nitrogen by ¹⁵N-enriched nitrogen are within the scope of thisinvention.

The compounds of formula (I) as well as their salts or solvates of thecompounds are preferably in pharmaceutically acceptable or substantiallypure form. By pharmaceutically acceptable form is meant, inter alia,having a pharmaceutically acceptable level of purity excluding normalpharmaceutical additives such as diluents and carriers, and including nomaterial considered toxic at normal dosage levels. Purity levels for thedrug substance are preferably above 50%, more preferably above 70%, mostpreferably above 90%. In a preferred embodiment it is above 95% of thecompound of formula (I) or, or of its salts. This applies also to itssolvates or prodrugs.

In a preferred embodiment the compound according to the inventionaccording to general formula I is a compound of formula I′

-   -   wherein q is 1, 2, 3 or 4,    -   R₁ and R₂ are as defined above for the compound of formula (I);        optionally in form of one of the stereoisomers, preferably        enantiomers or diastereomers, a racemate or in form of a mixture        of at least two of the stereoisomers, preferably enantiomers        and/or diastereomers, in any mixing ratio, or a corresponding        salt thereof, or a corresponding solvate thereof.

In another preferred embodiment the compound according to the inventionof general formula I is a compound of formula I″

-   -   wherein R₁, R₂ and R₃ are as defined above for the compound of        formula (I);        optionally in form of one of the stereoisomers, preferably        enantiomers or diastereomers, a racemate or in form of a mixture        of at least two of the stereoisomers, preferably enantiomers        and/or diastereomers, in any mixing ratio, or a corresponding        salt thereof, or a corresponding solvate thereof.

In a particular embodiment one or more of the following compounds areexcluded:

-   2,4-dimethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,    and/or-   2-ethyl-4-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,    and/or-   2-isopropyl-4-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,    and/or-   2-butyl-4-ethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one.

-   -   In a particular embodiment this exclusion only refers to the        respective racemic form of this or these compound/s above.    -   In a particular embodiment all these 4 compounds above are        excluded.

In another particular embodiment, the condition/proviso applies for acompound according to Formula I″ that if R₂ is unsubstituted phenyl andR₃ is CO₁₄-alkyl, then R₁ may not be C₁₋₂-alkyl.

In a preferred embodiment of the compound according to the inventionaccording to general formulas I, I′ or I″ is a compound wherein

R₁ is unsubstituted C₁₋₆ alkyl, unsubstituted C₂₋₆ alkenyl,unsubstituted C₂₋₆ alkynyl, unsubstituted C₃₋₆ cycloalkyl, unsubstitutedC₄₋₇ alkylcycloalkyl;R₂ is substituted or unsubstituted monocyclic aryl or substituted orunsubstituted monocyclic heterocyclyl;R₃—for Formula I or I″—is unsubstituted C₁₋₆ alkyl, unsubstituted C₂₋₆alkenyl, unsubstituted C₂₋₆ alkynyl, unsubstituted C₃₋₆ cycloalkyl,unsubstituted C₄₋₇ alkylcycloalkyl, unsubstituted C₄₋₇ alkylaryl,unsubstituted C₃₋₆ aryl, unsubstituted C₃₋₆ heterocyclyl orunsubstituted C₄₋₇ alkylheterocyclyl;R_(3′)—for Formula I—is hydrogen or unsubstituted C₁₋₆ alkyl,unsubstituted C₂₋₆ alkenyl or unsubstituted C₂₋₆ alkynyl;alternatively R₃ and R_(3′) taken together (with the connecting C-atom)may form an unsubstituted C₃₋₆ cycloalkyl;R₄, R_(4′) and R_(4″) are independently selected from hydrogen orunsubstituted C₁₋₆ alkyl, unsubstituted C₂₋₆ alkenyl or unsubstitutedC₂₋₆ alkynyl, unsubstituted C₃₋₆ cycloalkyl;andR_(4″′) is hydrogen or unsubstituted C₁₋₆ alkyl, unsubstituted C₂₋₆alkenyl, unsubstituted C₂₋₆ alkynyl or -Boc;optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof, or a correspondingsolvate thereof.

In another preferred embodiment the compound according to the inventionaccording to general formula I is a compound of formula I′,

wherein q is 1;optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof, or a correspondingsolvate thereof.

In another preferred embodiment of the compound according to theinvention according to general formulas I, I′, or I″ the compound is acompound, wherein

R₁ is substituted or unsubstituted C₁₋₆ alkyl, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₃₋₆ cycloalkyl, substituted orunsubstituted C₄₋₇ alkylcycloalkyl,optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof, or a correspondingsolvate thereof.

In another preferred embodiment of the compound according to theinvention according to general formulas I, I′, or I″ the compound is acompound, wherein

R₂ is substituted or unsubstituted monocyclic aryl or substituted orunsubstituted monocyclic heterocyclyl,optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof, or a correspondingsolvate thereof.

In another preferred embodiment of the compound according to theinvention according to general formulas I, or I″ the compound is acompound, wherein

R₃ is substituted or unsubstituted C₁₋₆ alkyl, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₃₋₆ cycloalkyl, substituted orunsubstituted C₄₋₇ alkylcycloalkyl, substituted or unsubstituted C₄₋₇alkylaryl, substituted or unsubstituted C₃₋₆ aryl, substituted orunsubstituted C₃₋₆ heterocyclyl or substituted or unsubstituted C₄₋₇alkylheterocyclyl;optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof, or a correspondingsolvate thereof.

In another preferred embodiment of the compound according to theinvention according to general formulas I the compound is a compound,wherein

R_(3′) is hydrogen or unsubstituted C₁₋₆ alkyl, unsubstituted C₂₋₆alkenyl or unsubstituted C₂₋₆ alkynyl,optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof, or a correspondingsolvate thereof.

In another preferred embodiment of the compound according to theinvention according to general formulas I the compound is a compound,wherein

R₃ and R_(3′) taken together (with the connecting C-atom) may form ansubstituted or unsubstituted C₃₋₆ cycloalkyl;optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof, or a correspondingsolvate thereof.

In another preferred embodiment of the compound according to theinvention according to general formulas I, I′, or I″ the compound is acompound, wherein

R₄, R_(4′) and R_(4″) are independently selected from hydrogen orsubstituted or unsubstituted C₁₋₆ alkyl, substituted or unsubstitutedC₂₋₆ alkenyl or substituted or unsubstituted C₂₋₆ alkynyl, substitutedor unsubstituted C₃₋₆ cycloalkyl;optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof, or a correspondingsolvate thereof.

In another preferred embodiment of the compound according to theinvention according to general formulas I, I′, or I″ the compound is acompound, wherein

R_(4″′) is hydrogen or unsubstituted C₁₋₆ alkyl, unsubstituted C₂₋₆alkenyl, unsubstituted C₂₋₆ alkynyl or -Boc;optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof, or a correspondingsolvate thereof.

In another preferred embodiment of the compound according to theinvention according to general formulas I, I′, or I″ the compound is acompound, wherein

R₁ is unsubstituted C₁₋₆ alkyl, unsubstituted C₂₋₆ alkenyl,unsubstituted C₂₋₆ alkynyl, unsubstituted C₃₋₆ cycloalkyl, unsubstitutedC₄₋₇ alkylcycloalkyl,optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof, or a correspondingsolvate thereof.

In another preferred embodiment of the compound according to theinvention according to general formulas I, I′, or I″ the compound is acompound, wherein

R₂ is substituted or unsubstituted monocyclic aryl or substituted orunsubstituted monocyclic heterocyclyl,optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof, or a correspondingsolvate thereof.

In another preferred embodiment of the compound according to theinvention according to general formulas I or I″ the compound is acompound, wherein

R₃ is unsubstituted C₁₋₆ alkyl, unsubstituted C₂₋₆ alkenyl,unsubstituted C₂₋₆ alkynyl, unsubstituted C₃₋₆ cycloalkyl, unsubstitutedC₄₋₇ alkylcycloalkyl, unsubstituted C₄₋₇ alkylaryl, unsubstituted C₃₋₆aryl, unsubstituted C₃₋₆ heterocyclyl or unsubstituted C₄₋₇alkylheterocyclyl;optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof, or a correspondingsolvate thereof.

In another preferred embodiment of the compound according to theinvention according to general formulas I the compound is a compound,wherein

R_(3′) is hydrogen or unsubstituted C₁₋₆ alkyl, unsubstituted C₂₋₆alkenyl or unsubstituted C₂₋₆ alkynyl,optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof, or a correspondingsolvate thereof.

In another preferred embodiment of the compound according to theinvention according to general formulas I the compound is a compound,wherein

R₃ and R_(3′) taken together (with the connecting C-atom) may form anunsubstituted C₃₋₆ cycloalkyl;optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof, or a correspondingsolvate thereof.

In another preferred embodiment of the compound according to theinvention according to general formulas I, I′, or I″ the compound is acompound, wherein

R₄, R_(4′) and R_(4″) are independently selected from hydrogen orunsubstituted C₁₋₆ alkyl, unsubstituted C₂₋₆ alkenyl or unsubstitutedC₂₋₆ alkynyl, unsubstituted C₃₋₆ cycloalkyl;optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof, or a correspondingsolvate thereof.

In another preferred embodiment of the compound according to theinvention according to general formulas I, I′, or I″ the compound is acompound, wherein

R_(4″′) is hydrogen or unsubstituted C₁₋₆ alkyl, unsubstituted C₂₋₆alkenyl, unsubstituted C₂₋₆ alkynyl or -Boc;optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof, or a correspondingsolvate thereof.

In another preferred embodiment of the compound according to theinvention according to general formulas I′ the compound is a compound,wherein

q is 1, 2, 3 or 4optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof, or a correspondingsolvate thereof.

In another preferred embodiment of the compound according to theinvention according to general formulas I, I′, or I″ the compound is acompound, wherein

in R₁ as defined in any of the above embodiments,the alkyl is C₁₋₄ alkyl like methyl, ethyl, propyl or butyl;the C₁₋₆ alkyl is preferably selected from methyl, ethyl, propyl, butyl,pentyl, hexyl, isopropyl, or 2-methylpropyl, preferably the C₁₋₆ alkylis methyl, ethyl, isopropyl;and/orthe C₂₋₆-alkenyl, is preferably selected from ethylene, propylene,butylene, pentylene or hexylene;and/orthe C₂₋₆-alkynyl is preferably selected from ethyne, propyne, butyne,pentyne or hexyne;and/orthe C₃₋₆ cycloalkyl is preferably selected from cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl; preferably the C₃₋₆ cycloalkyl iscyclopropyl;and/orin R₂ as defined in any of the above embodiments,the aryl is phenyl;and/orthe heterocyclyl is a heterocyclic ring system of one saturated orunsaturated ring which contains one or more heteroatoms from the groupconsisting of nitrogen, oxygen and/or sulfur in the ring; morepreferably is selected from imidazole, oxadiazole, tetrazole, pyridine,pyrimidine, piperidine, piperazine, thiazole, tetrahydropyrane,morpholine, furan, triazole, isoxazole, pyrazole, thiophene, pyrrole,pyrazine, oxopyrrolidine, pyrimidine, preferably the heterocyclyl ispyridine or thiazole;and/orin R₃—for Formula I or I″—as defined in any of the above embodiments,the alkyl is C₁₋₄ alkyl like methyl, ethyl, propyl or butyl;the C₁₋₆ alkyl is preferably selected from methyl, ethyl, propyl, butyl,pentyl, hexyl, isopropyl, or 2-methylpropyl, preferably the C₁₋₆ alkylis methyl, ethyl, isopropyl,and/orthe C₂₋₆-alkenyl, is preferably selected from ethylene, propylene,butylene, pentylene or hexylene;and/orthe C₂₋₆-alkynyl like ethyne, propyne, butyne, pentyne or hexyne,preferably propyne;and/orthe aryl is phenyl;and/orthe heterocyclyl is a heterocyclic ring system of one or more saturatedor unsaturated rings of which at least one ring contains one or moreheteroatoms from the group consisting of nitrogen, oxygen and/or sulfurin the ring; preferably is a heterocyclic ring system of one or twosaturated or unsaturated rings of which at least one ring contains oneor more heteroatoms from the group consisting of nitrogen, oxygen and/orsulfur in the ring, more preferably is selected from imidazole,oxadiazole, tetrazole, pyridine, pyrimidine, piperidine, piperazine,benzofuran, benzimidazole, indazole, benzothiazole, benzodiazole,thiazole, benzothiazole, tetrahydropyrane, morpholine, indoline, furan,triazole, isoxazole, pyrazole, thiophene, benzothiophene, pyrrole,pyrazine, pyrrolo[2,3b]pyridine, quinoline, isoquinoline, phthalazine,benzo-1,2,5-thiadiazole, indole, benzotriazole, benzoxazoleoxopyrrolidine, pyrimidine, benzodioxolane, benzodioxane, carbazole andquinazoline;and/orthe C₃₋₆ cycloalkyl is preferably selected from cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl;and/orin R_(3′)—for Formula I—as defined in any of the above embodiments,the C₁₋₆ alkyl is preferably selected from methyl, ethyl, propyl, butyl,pentyl, hexyl, isopropyl, or 2-methylpropyl, preferably, the C₁₋₆ alkylis methyl or ethyl;and/orthe C₂₋₆-alkenyl, is preferably selected from ethylene, propylene,butylene, pentylene or hexylene;and/orthe C₂₋₆-alkynyl is preferably selected from ethyne, propyne, butyne,pentyne or hexyne;and/orin R₃ and R_(3′)—for Formula I—taken together (with the connectingC-atom) and forming a cycloalkyl as defined in any of the aboveembodiments,the C₃₋₆ cycloalkyl is preferably selected from cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl, preferably the C₃₋₆ cycloalkyl is cyclopropylor cyclopentyl;and/orin R₄, R_(4′) and R_(4″) as defined in any of the above embodiments,the C₁₋₆ alkyl is preferably selected from methyl, ethyl, propyl, butyl,pentyl, hexyl, isopropyl, or 2-methylpropyl, preferably the C₁₋₆ alkylis methyl;and/orthe C₂₋₆-alkenyl, is preferably selected from ethylene, propylene,butylene, pentylene or hexylene;and/orthe C₂₋₆-alkynyl is preferably selected from ethyne, propyne, butyne,pentyne or hexyne;and/orthe C₃₋₆ cycloalkyl is preferably selected from cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl;and/orin R_(4″′) as defined in any of the above embodiments,the C₁₋₆ alkyl is preferably selected from methyl, ethyl, propyl, butyl,pentyl, hexyl, isopropyl, or 2-methylpropyl,and/orthe C₂₋₆-alkenyl, is preferably selected from ethylene, propylene,butylene, pentylene or hexylene;and/orthe C₂₋₆-alkynyl is preferably selected from ethyne, propyne, butyne,pentyne or hexyne;optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof, or a correspondingsolvate thereof.

In another preferred embodiment of the compound according to theinvention according to general formulas I, I′, or I″ the compound is acompound, wherein

in R₁ as defined in any of the above embodiments,the alkyl is C₁₋₄ alkyl like methyl, ethyl, propyl or butyl;the C₁₋₆ alkyl is preferably selected from methyl, ethyl, propyl, butyl,pentyl, hexyl, isopropyl, or 2-methylpropyl, preferably the C₁₋₆ alkylis methyl, ethyl, isopropyl;and/orthe C₂₋₆-alkenyl, is preferably selected from ethylene, propylene,butylene, pentylene or hexylene;and/orthe C₂₋₆-alkynyl is preferably selected from ethyne, propyne, butyne,pentyne or hexyne;and/orthe C₃₋₆ cycloalkyl is preferably selected from cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl; preferably the C₃₋₆ cycloalkyl iscyclopropyl;optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof, or a correspondingsolvate thereof.

In another preferred embodiment of the compound according to theinvention according to general formulas I, I′, or I″ the compound is acompound, wherein

in R₂ as defined in any of the above embodiments,the aryl is phenyl;and/orthe heterocyclyl is a heterocyclic ring system of one saturated orunsaturated ring which contains one or more heteroatoms from the groupconsisting of nitrogen, oxygen and/or sulfur in the ring; morepreferably is selected from imidazole, oxadiazole, tetrazole, pyridine,pyrimidine, piperidine, piperazine, thiazole, tetrahydropyrane,morpholine, furan, triazole, isoxazole, pyrazole, thiophene, pyrrole,pyrazine, oxopyrrolidine, pyrimidine, preferably the heterocyclyl ispyridine or thiazole;optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof, or a correspondingsolvate thereof.

In another preferred embodiment of the compound according to theinvention according to general formulas I or I″ the compound is acompound, wherein

in R₃ as defined in any of the above embodiments,the alkyl is C₁₋₄ alkyl like methyl, ethyl, propyl or butyl;the C₁₋₆ alkyl is preferably selected from methyl, ethyl, propyl, butyl,pentyl, hexyl, isopropyl, or 2-methylpropyl, preferably the C₁₋₆ alkylis methyl, ethyl, isopropyl,and/orthe C₂₋₆-alkenyl, is preferably selected from ethylene, propylene,butylene, pentylene or hexylene;and/orthe C₂₋₆-alkynyl is preferably selected from ethyne, propyne, butyne,pentyne or hexyne, preferably propyne;and/orthe aryl is phenyl;and/orthe heterocyclyl is a heterocyclic ring system of one or more saturatedor unsaturated rings of which at least one ring contains one or moreheteroatoms from the group consisting of nitrogen, oxygen and/or sulfurin the ring; preferably is a heterocyclic ring system of one or twosaturated or unsaturated rings of which at least one ring contains oneor more heteroatoms from the group consisting of nitrogen, oxygen and/orsulfur in the ring, more preferably is selected from imidazole,oxadiazole, tetrazole, pyridine, pyrimidine, piperidine, piperazine,benzofuran, benzimidazole, indazole, benzothiazole, benzodiazole,thiazole, benzothiazole, tetrahydropyrane, morpholine, indoline, furan,triazole, isoxazole, pyrazole, thiophene, benzothiophene, pyrrole,pyrazine, pyrrolo[2,3b]pyridine, quinoline, isoquinoline, phthalazine,benzo-1,2,5-thiadiazole, indole, benzotriazole, benzoxazoleoxopyrrolidine, pyrimidine, benzodioxolane, benzodioxane, carbazole andquinazoline,and/orthe C₃₋₆ cycloalkyl is preferably selected from cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl,optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof, or a correspondingsolvate thereof.

In another preferred embodiment of the compound according to theinvention according to general formulas I the compound is a compound,wherein

in R_(3′) as defined in any of the above embodiments,the C₁₋₆ alkyl is preferably selected from methyl, ethyl, propyl, butyl,pentyl, hexyl, isopropyl, or 2-methylpropyl, preferably, the C₁₋₆ alkylis methyl or ethyl;and/orthe C₂₋₆-alkenyl, is preferably selected from ethylene, propylene,butylene, pentylene or hexylene;and/orthe C₂₋₆-alkynyl is preferably selected from ethyne, propyne, butyne,pentyne or hexyne;optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof, or a correspondingsolvate thereof.

In another preferred embodiment of the compound according to theinvention according to general formula I the compound is a compound,wherein

in R₃ and R_(3′) taken together (with the connecting C-atom) and forminga cycloalkyl as defined in any of the above embodiments,the C₃₋₆ cycloalkyl is preferably selected from cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl, preferably the C₃₋₆ cycloalkyl is cyclopropylor cyclopentyl;optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof, or a correspondingsolvate thereof.

In another preferred embodiment of the compound according to theinvention according to general formulas I, I′, or I″ the compound is acompound, wherein

in R₄, R_(4′) and R_(4″) as defined in any of the above embodiments,the C₁₋₆ alkyl is preferably selected from methyl, ethyl, propyl, butyl,pentyl, hexyl, isopropyl, or 2-methylpropyl, preferably the C₁₋₆ alkylis methyl;and/orthe C₂₋₆-alkenyl, is preferably selected from ethylene, propylene,butylene, pentylene or hexylene;and/orthe C₂₋₆-alkynyl is preferably selected from ethyne, propyne, butyne,pentyne or hexyne;and/orthe C₃₋₆ cycloalkyl is preferably selected from cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl;optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof, or a correspondingsolvate thereof.

In another preferred embodiment of the compound according to theinvention according to general formulas I, I′, or I″ the compound is acompound, wherein

in R_(4″′) as defined in any of the above embodiments,the C₁₋₆ alkyl is preferably selected from methyl, ethyl, propyl, butyl,pentyl, hexyl, isopropyl, or 2-methylpropyl,and/orthe C₂₋₆-alkenyl, is preferably selected from ethylene, propylene,butylene, pentylene or hexylene;and/orthe C₂₋₆-alkynyl is preferably selected from ethyne, propyne, butyne,pentyne or hexyne;optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof, or a correspondingsolvate thereof.

In a preferred embodiment

R₁ is substituted or unsubstituted methyl, substituted or unsubstitutedethyl, substituted or unsubstituted isopropyl or substituted orunsubstituted cyclopropyl, preferably R₁ is unsubstituted methyl,unsubstituted ethyl, unsubstituted isopropyl or unsubstitutedcyclopropyl;

In another preferred embodiment R₂ is substituted or unsubstitutedphenyl, substituted or unsubstituted pyridine or substituted orunsubstituted thiazole.

In a most preferred embodiment

R₃ is substituted or unsubstituted methyl, substituted or unsubstitutedethyl, substituted or unsubstituted isopropyl, substituted orunsubstituted propyne, substituted or unsubstituted benzyl or —CH₂CH₂OH,preferably R₃ is unsubstituted methyl, unsubstituted ethyl,unsubstituted isopropyl, unsubstituted propyne, unsubstituted benzyl or—CH₂CH₂OH.

In a preferred embodiment

R_(3′) is hydrogen, substituted or unsubstituted methyl or substitutedor unsubstituted ethyl, preferably R_(3′) is hydrogen, unsubstitutedmethyl or unsubstituted ethyl.

In another preferred embodiment

R₃ is substituted or unsubstituted methyl, substituted or unsubstitutedethyl, substituted or unsubstituted isopropyl, substituted orunsubstituted propyne, substituted or unsubstituted benzyl or —CH₂CH₂OH,while R_(3′) is hydrogen, substituted or unsubstituted methyl orsubstituted or unsubstituted ethyl,

In another preferred embodiment

R₃ is unsubstituted methyl, unsubstituted ethyl, unsubstitutedisopropyl, unsubstituted propyne, unsubstituted benzyl or —CH₂CH₂OH,while R_(3′) is hydrogen, unsubstituted methyl or unsubstituted ethyl,

In a preferred embodiment

R₃ is unsubstituted methyl, unsubstituted ethyl, unsubstitutedisopropyl, unsubstituted benzyl, unsubstituted propyne or —CH₂CH₂OHwhile R_(3′) is hydrogen.

In another preferred embodiment

R₃ is substituted or unsubstituted methyl while R_(3′) is substituted orunsubstituted methyl, preferably, R₃ is unsubstituted methyl whileR_(3′) is unsubstituted methyl.

In another preferred embodiment

R₃ is substituted or unsubstituted ethyl while R_(3′) is substituted orunsubstituted ethyl, preferably R₃ is unsubstituted ethyl while R_(3′)is unsubstituted ethyl.

In another preferred embodiment

R₃ is substituted or unsubstituted propyne while R_(3′) is hydrogen,preferably R₃ is unsubstituted propyne while R_(3′) is hydrogen,

In another preferred embodiment

R₃ is substituted or unsubstituted benzyl while R_(3′) is hydrogen,preferably R₃ is unsubstituted benzyl while R_(3′) is hydrogen.

In another preferred embodiment

R₃ is —CH₂CH₂OH while R_(3′) is hydrogen.

In another preferred embodiment

R₃ and R_(3′) taken together (with the connecting C-atom) is substitutedor unsubstituted cyclopropyl or substituted or unsubstitutedcyclopentyl, preferably, R₃ and R_(3′) taken together (with theconnecting C-atom) is unsubstituted cyclopropyl or unsubstitutedcyclopentyl

In a preferred embodiment

R₄, R_(4′) and R_(4″) are hydrogen or substituted or unsubstitutedmethyl.

In a preferred embodiment

R₄, R_(4′) and R_(4″) are hydrogen or unsubstituted methyl.

In another preferred embodiment

R_(4″′) is hydrogen or -Boc.

In another preferred embodiment

R_(4″′) is unsubstituted methyl.

In particular preferred embodiment

R₄, R_(4′) and R_(4″) are hydrogen or substituted or unsubstitutedmethyl, while R_(4″′) is hydrogen or -Boc.

In particular preferred embodiment

R₄, R_(4′) and R_(4″) are hydrogen or unsubstituted methyl, whileR_(4″′) is hydrogen or -Boc.

In another particular preferred embodiment

q is 1.

In an embodiment of the invention in the compound of general formulas I,I′, and I″

the halogen is fluorine, chlorine, iodine or bromine.

In a most preferred embodiment of the invention in the compoundaccording to general formulas I, I′, and I″

the halogen is fluorine or chlorine.

In an embodiment of the invention in the compound of general formulas I,I′, and I″

the haloalkyl is —CF3.

In another embodiment of the invention in the compound of generalformulas I, I′, and I″

the haloalkoxy is —OCF3.

In another preferred embodiment of the compound according to theinvention according to general formulas I, I′, or I″ the compound is acompound, wherein

R₁ is substituted or unsubstituted C₁₋₆ alkyl, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₃₋₆ cycloalkyl, substituted orunsubstituted C₄₋₇ alkylcycloalkyl,wherein the cycloalkyl in R₁ if substituted (also in alkylcycloalkyl) issubstituted with substituents selected from —R_(4″′), halogen,—SR_(4″′), —CN, haloalkyl, —NR_(4″′)R_(4″′),optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof.

In another preferred embodiment of the compound according to theinvention according to general formulas I, I′, or I″ the compound is acompound, wherein

R₁ is substituted or unsubstituted C₁₋₆ alkyl, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₃₋₆ cycloalkyl, substituted orunsubstituted C₄₋₇ alkylcycloalkyl,wherein the alkyl, alkenyl and alkynyl in R₁ if substituted aresubstituted with substituents selected from halogen, —CN, haloalkyl;optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof.

In another preferred embodiment of the compound according to theinvention according to general formulas I, I′, or I″ the compound is acompound, wherein

R₂ is substituted or unsubstituted monocyclic aryl or substituted orunsubstituted monocyclic heterocyclyl,wherein the aryl, or heterocyclyl in R₂ if substituted is substitutedwith substituents selected from —R₄, —OR₄, halogen, ═O, —OCH₂CH₂OH,—SR₄, —S(O)R₄, —S(O)₂R₄, —CN, haloalkyl-haloalkoxy, —NR₄R_(4″′), —NO₂,—NR₄C(O)R_(4′), —NR₄SO₂R_(4′), —C(O)OR₄, —C(O)NR₄R_(4′),—NR₄C(O)NR_(4′)R_(4″), —S(O)₂NR₄R_(4′), —NR₄S(O)₂NR_(4′)R_(4″),optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof.

In another preferred embodiment of the compound according to theinvention according to general formulas I, I′, or I″ the compound is acompound, wherein

R₂ is substituted or unsubstituted monocyclic aryl or substituted orunsubstituted monocyclic heterocyclyl,wherein the aryl or heterocyclyl in R₂ if substituted is substitutedwith substituents selected from —R_(4″′), —OR_(4″′), halogen, ═O,—OCH₂CH₂OH, —SR_(4″′), —S(O)R_(4″′), —S(O)₂R_(4″′), —CN,haloalkyl-haloalkoxy, —NR_(4″′)R_(4″′), —NO₂, —NR_(4″′)C(O)R_(4″′),—NR_(4″′)S(O)₂R_(4″′), —C(O)OR_(4″′), —C(O)NR_(4″′)R_(4″′),—NR_(4″′)C(O)NR_(4″′)R_(4″′), —S(O)₂NR_(4″′)R_(4″′),—NR_(4″′)S(O)₂NR_(4″′)R_(4″′)optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof.

In another preferred embodiment of the compound according to theinvention according to general formulas I or I″ the compound is acompound, wherein

R₃ is substituted or unsubstituted C₁₋₆ alkyl, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₃₋₆ cycloalkyl, substituted orunsubstituted C₄₋₇ alkylcycloalkyl, substituted or unsubstituted C₄₋₇alkylaryl, substituted or unsubstituted C₃₋₆ aryl, substituted orunsubstituted C₃₋₆ heterocyclyl or substituted or unsubstituted C₄₋₇alkylheterocyclyl;wherein the aryl, heterocyclyl or cycloalkyl in R₃ if substituted (alsoin alkylaryl, alkylcycloalkyl or alkylheterocyclyl) is substituted withsubstituents selected from —R₄, —OR₄, halogen, ═O, —OCH₂CH₂OH, —SR₄,—S(O)R₄, —S(O)₂R₄, —CN, haloalkyl, -haloalkoxy, —NR₄R_(4″′), —NO₂,—NR₄C(O)R_(4′), —NR₄S(O)₂R_(4′), —C(O)OR₄, —C(O)NR₄R_(4′),—NR₄C(O)NR_(4′)R_(4″), —S(O)₂NR₄R_(4′), —NR₄S(O)₂NR_(4′)R_(4″)optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof.

In another preferred embodiment of the compound according to theinvention according to general formulas I or I″ the compound is acompound, wherein

R₃ is substituted or unsubstituted C₁₋₆ alkyl, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₃₋₆ cycloalkyl, substituted orunsubstituted C₄₋₇ alkylcycloalkyl, substituted or unsubstituted C₄₋₇alkylaryl, substituted or unsubstituted C₃₋₆ aryl, substituted orunsubstituted C₃₋₆ heterocyclyl or substituted or unsubstituted C₄₋₇alkylheterocyclyl;wherein the aryl, heterocyclyl or cycloalkyl in R₃ if substituted (alsoin alkylaryl, alkylcycloalkyl or alkylheterocyclyl) is substituted withsubstituents selected from —R_(4″′), —OR_(4″′), halogen, ═O, —OCH₂CH₂OH,—SR_(4″′), —S(O)R_(4″′), —S(O)₂R_(4″′), —CN, haloalkyl, -haloalkoxy,—NR_(4″′)R_(4″′), —NO₂, —NR_(4″′)C(O)R4″′, —NR_(4″′)S(O)₂R_(4″′),—C(O)OR_(4″′), —C(O)NR_(4″′)R_(4″′), —NR_(4″′)C(O)NR_(4″′)R_(4″′),—S(O)₂NR_(4″′)R_(4″′), —NR_(4″′)S(O)₂NR_(4″′)R_(4″′)optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof.

In another preferred embodiment of the compound according to theinvention according to general formulas I or I″ the compound is acompound, wherein

R₃ is substituted or unsubstituted C₁₋₆ alkyl, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₃₋₆ cycloalkyl, substituted orunsubstituted C₄₋₇ alkylcycloalkyl, substituted or unsubstituted C₄₋₇alkylaryl, substituted or unsubstituted C₃₋₆ aryl, substituted orunsubstituted C₃₋₆ heterocyclyl or substituted or unsubstituted C₄₋₇alkylheterocyclyl;and wherein the alkyl, alkenyl and alkynyl in R₃ if substituted aresubstituted with substituents selected from —OR₄, halogen, —CN,haloalkyl, optionally in form of one of the stereoisomers, preferablyenantiomers or diastereomers, a racemate or in form of a mixture of atleast two of the stereoisomers, preferably enantiomers and/ordiastereomers, in any mixing ratio, or a corresponding salt thereof.

In another preferred embodiment of the compound according to theinvention according to general formulas I or I″ the compound is acompound, wherein

R₃ is substituted or unsubstituted C₁₋₆ alkyl, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₃₋₆ cycloalkyl, substituted orunsubstituted C₄₋₇ alkylcycloalkyl, substituted or unsubstituted C₄₋₇alkylaryl, substituted or unsubstituted C₃₋₆ aryl, substituted orunsubstituted C₃₋₆ heterocyclyl or substituted or unsubstituted C₄₋₇alkylheterocyclyl;and wherein the alkyl, alkenyl and alkynyl in R₃ if substituted aresubstituted with substituents selected from —OR_(4″′), halogen, —CN,haloalkyl,optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof.

In another preferred embodiment of the compound according to theinvention according to general formula I the compound is a compound,wherein

R₃ and R_(3′) taken together (with the connecting C-atom) may form ansubstituted or unsubstituted C₃₋₆ cycloalkyl;wherein the cycloalkyl for R₃ and R_(3′) taken together if substitutedis substituted with substituents selected from —R₄, —OR₄, halogen, ═O,—OCH₂CH₂OH, —SR₄, —S(O)R₄, —S(O)₂R₄, —CN, haloalkyl, -haloalkoxy,—NR₄R_(4″′), —NO₂, —NR₄C(O)R_(4′), —NR₄S(O)₂R_(4′), —C(O)OR₄,—C(O)NR₄R_(4′), —NR₄C(O)NR_(4′)R_(4″), —S(O)₂NR₄R_(4′),—NR₄S(O)₂NR_(4′)R_(4″)optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof.

In another preferred embodiment of the compound according to theinvention according to general formulas I the compound is a compound,wherein

R₃ and R_(3′) taken together (with the connecting C-atom) may form ansubstituted or unsubstituted C₃₋₆ cycloalkyl;wherein the cycloalkyl for R₃ and R_(3′) taken together if substitutedis substituted with substituents selected from —R_(4″′), —OR_(4″′),halogen, ═O, —OCH₂CH₂OH, —SR_(4″′), —S(O)R_(4″′), —S(O)₂R_(4″′), —CN,haloalkyl, -haloalkoxy, —NR_(4″′)R_(4″′), —NO₂, —NR_(4″′)C(O)R4″′,—NR_(4″′)S(O)₂R_(4″′), —C(O)OR_(4″′), —C(O)NR_(4″′)R_(4″′),—NR_(4″′)C(O)NR_(4″′)R_(4″′), —S(O)₂NR_(4″′)R_(4″′),—NR_(4″′)S(O)₂NR_(4″′)R_(4″′)optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof.

In another preferred embodiment of the compound according to theinvention according to general formulas I, I′, or I″ the compound is acompound, wherein

R₄, R_(4′) and R_(4″) are independently selected from hydrogen orsubstituted or unsubstituted C₁₋₆ alkyl, substituted or unsubstitutedC₂₋₆ alkenyl or substituted or unsubstituted C₂₋₆ alkynyl, substitutedor unsubstituted C₃₋₆ cycloalkyl; wherein the cycloalkyl in R₄ R_(4′) orR_(4″) if substituted is substituted with substituents selected from—R_(4″′), halogen, —SR_(4″′), —CN, haloalkyl, —NR_(4″′)R_(4″′),optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof.

In another preferred embodiment of the compound according to theinvention according to general formulas I, I′, or I″ the compound is acompound, wherein

R₄, R_(4′) and R_(4″) are independently selected from hydrogen orsubstituted or unsubstituted C₁₋₆ alkyl, substituted or unsubstitutedC₂₋₆ alkenyl or substituted or unsubstituted C₂₋₆ alkynyl, substitutedor unsubstituted C₃₋₆ cycloalkyl; wherein the alkyl, alkenyl and alkynylin R₄ R_(4′) or R_(4″) if substituted are substituted with substituentsselected from halogen, —CN, haloalkyloptionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof.

In one preferred further embodiment, the compounds of the generalformula I are selected from

Ex Chemical name 112-ethyl-8-{2-[3-(trifluoromethyl)pyridin-2-yl]ethyl}-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one 212-ethyl-8-{2-[6-(trifluoromethyl)pyridin-2-yl]ethyl}-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one 312-ethyl-8-[2-(3-fluoropyridin-2-yl)ethyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one 412-ethyl-8-{2-[4-(trifluoromethyl)pyridin-2-yl]ethyl}-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one 58-[2-(3-chloropyridin-2-yl)ethyl]-12-ethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one 68-[2-(6-aminopyridin-2-yl)ethyl]-12-ethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one 712-ethyl-8-phenethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one 812-isopropyl-8-phenethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one912-isopropyl-8-[2-(pyridin-2-yl)ethyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one dihydrochloride 1012-ethyl-8-[2-(pyridin-2-yl)ethyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one11 (R)-2,4-dimethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one12 12-ethyl-8-{2-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one 1312-ethyl-8-[2-(6-methoxypyridin-2-yl)ethyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one 1412-ethyl-8-[2-(6-hydroxypyridin-2-yl)ethyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one 154-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)benzene-1-sulfonamide 164-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)-N-methylbenzene-1-sulfonamide 1712-ethyl-8-{2-[3-(trifluoromethoxy)phenyl]ethyl}-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one 18(R)-4-ethyl-2-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one1912-ethyl-8-(3-nitrophenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one2012-ethyl-8-(3-methoxyphenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one 21 tert-butyl(4-(2-(12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl)ethyl)thiazol-2-yl)carbamate 22 methyl4-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)benzoate 2312-ethyl-8-[2-(pyridin-4-yl)ethyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one2412-ethyl-8-[2-(pyridin-3-yl)ethyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one2512-ethyl-8-(4-methoxyphenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one 2612-ethyl-8-(2-methoxyphenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one 27 3-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)benzonitrile 284-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)-N,N-dimethylbenzamide 298-[2-fluorophenethyl]-12-methyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one308-[2-fluorophenethyl]-12-isopropyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one 31(R)-2-isopropyl-4-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one32(R)-4-ethyl-9-(2-fluorophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 33(R)-2-ethyl-4-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one34 (R)-9-(3-fluorophenethyl)-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 35(R)-4-cyclopropyl-9-(2-fluorophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 36(R)-4-isopropyl-2-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one37(R)-9-(2-fluorophenethyl)-2,4-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one38(R)-9-(3-fluorophenethyl)-2,4-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one39 (R)-9-(2-fluorophenethyl)-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 40(R)-4-cyclopropyl-2-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one41 (R)-4-cyclopropyl-9-(3-fluorophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 42(R)-4-ethyl-9-(3-fluorophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 438-(3-fluorophenethyl)-12-isopropyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one hydrochloride 44(R)-2,4-dimethyl-9-(3-(trifluoromethyl)phenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 45(R)-2,4-dimethyl-9-(2-(trifluoromethoxy)phenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 46(R)-9-(2-fluorophenethyl)-2-isopropyl-4-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 47(R)-9-(3-fluorophenethyl)-2-isopropyl-4-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 48(R)-2,4-dimethyl-9-(2-(trifluoromethyl)phenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 49(R)-9-(2,6-difluorophenethyl)-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 50(R)-9-(2,5-difluorophenethyl)-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 51(R)-9-(2,3-difluorophenethyl)-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 52(R)-2-ethyl-9-(2-fluorophenethyl)-4-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 53(R)-2-ethyl-9-(3-fluorophenethyl)-4-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 542,2,4-trimethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 5512-methyl-8-phenethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one 568-(3-aminophenethyl)-12-ethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one57 N-[3-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)phenyl]acetamide 58[3-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)phenyl]urea 594-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)-N-methylbenzamide 6012-ethyl-8-(2-hydroxyphenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one 6112-ethyl-8-(3-hydroxyphenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one6212-ethyl-8-(4-hydroxyphenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one hydrochloride, or 638-[2-(2-aminothiazol-4-yl)ethyl]-12-ethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one;optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof.

In another preferred further embodiment, the compounds of the generalformula I are selected from

Ex Chemical name 112-ethyl-8-{2-[3-(trifluoromethyl)pyridin-2-yl]ethyl}-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one 212-ethyl-8-{2-[6-(trifluoromethyl)pyridin-2-yl]ethyl}-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one 312-ethyl-8-[2-(3-fluoropyridin-2-yl)ethyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one 412-ethyl-8-{2-[4-(trifluoromethyl)pyridin-2-yl]ethyl}-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one 58-[2-(3-chloropyridin-2-yl)ethyl]-12-ethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one 68-[2-(6-aminopyridin-2-yl)ethyl]-12-ethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one 712-ethyl-8-phenethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one 812-isopropyl-8-phenethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one912-isopropyl-8-[2-(pyridin-2-yl)ethyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one dihydrochloride 1012-ethyl-8-[2-(pyridin-2-yl)ethyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one11 (R)-2,4-dimethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one12 12-ethyl-8-{2-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one 1312-ethyl-8-[2-(6-methoxypyridin-2-yl)ethyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one 1412-ethyl-8-[2-(6-hydroxypyridin-2-yl)ethyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one 154-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)benzene-1-sulfonamide 164-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)-N-methylbenzene-1-sulfonamide 1712-ethyl-8-{2-[3-(trifluoromethoxy)phenyl]ethyl}-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one 18(R)-4-ethyl-2-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one1912-ethyl-8-(3-nitrophenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one2012-ethyl-8-(3-methoxyphenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one 21 tert-butyl(4-(2-(12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl)ethyl)thiazol-2-yl)carbamate 22 methyl4-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)benzoate 2312-ethyl-8-[2-(pyridin-4-yl)ethyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one2412-ethyl-8-[2-(pyridin-3-yl)ethyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one2512-ethyl-8-(4-methoxyphenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one 2612-ethyl-8-(2-methoxyphenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one 27 3-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)benzonitrile 284-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)-N,N-dimethylbenzamide 298-[2-fluorophenethyl]-12-methyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one308-[2-fluorophenethyl]-12-isopropyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one 31(R)-2-isopropyl-4-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one32(R)-4-ethyl-9-(2-fluorophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 33(R)-2-ethyl-4-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one34 (R)-9-(3-fluorophenethyl)-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 35(R)-4-cyclopropyl-9-(2-fluorophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 36(R)-4-isopropyl-2-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one37(R)-9-(2-fluorophenethyl)-2,4-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one38(R)-9-(3-fluorophenethyl)-2,4-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one39 (R)-9-(2-fluorophenethyl)-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 40(R)-4-cyclopropyl-2-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one41 (R)-4-cyclopropyl-9-(3-fluorophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 42(R)-4-ethyl-9-(3-fluorophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 438-(3-fluorophenethyl)-12-isopropyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one hydrochloride 44(R)-2,4-dimethyl-9-(3-(trifluoromethyl)phenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 45(R)-2,4-dimethyl-9-(2-(trifluoromethoxy)phenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 46(R)-9-(2-fluorophenethyl)-2-isopropyl-4-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 47(R)-9-(3-fluorophenethyl)-2-isopropyl-4-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 48(R)-2,4-dimethyl-9-(2-(trifluoromethyl)phenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 49(R)-9-(2,6-difluorophenethyl)-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 50(R)-9-(2,5-difluorophenethyl)-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 51(R)-9-(2,3-difluorophenethyl)-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 52(R)-2-ethyl-9-(2-fluorophenethyl)-4-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 53(R)-2-ethyl-9-(3-fluorophenethyl)-4-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 542,2,4-trimethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 5512-methyl-8-phenethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one 568-(3-aminophenethyl)-12-ethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one57 N-[3-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)phenyl]acetamide 58[3-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)phenyl]urea 594-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)-N-methylbenzamide 6012-ethyl-8-(2-hydroxyphenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one 6112-ethyl-8-(3-hydroxyphenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one62 12-ethyl-8-(4-hydroxyphenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13- one hydrochloride 638-[2-(2-aminothiazol-4-yl)ethyl]-12-ethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one 642,2-diethyl-4-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one65 4-cyclopropyl-9-(2-fluorophenethyl)-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 668-(2,5-difluorophenethyl)-12-isopropyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one 678-(2,3-difluorophenethyl)-12-isopropyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one 6810-(2-fluorophenethyl)-14-methyl-6-oxa-10,14-diazadispiro[4.1.5.3]pentadecan-15-one 6910-(3-fluorophenethyl)-14-methyl-6-oxa-10,14-diazadispiro[4.1.5.3]pentadecan-15-one 70(R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 718-(2,5-difluorophenethyl)-12-ethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one 7212-ethyl-8-(3-fluorophenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one7312-ethyl-8-(2-fluorophenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one74(R)-9-(2,3-difluorophenethyl)-2,4-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 75(R)-2,4-diethyl-9-(2-fluorophenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one76(R)-2,4-diethyl-9-(3-fluorophenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one77(R)-2-ethyl-9-(3-fluorophenethyl)-4-isopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 784-ethyl-9-(3-fluorophenethyl)-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 794-ethyl-9-(2-fluorophenethyl)-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 80(R)-2-ethyl-9-(2-fluorophenethyl)-4-isopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 81(R)-9-(2,5-difluorophenethyl)-2,4-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 82 9-(3-fluorophenethyl)-4-isopropyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 839-(2-fluorophenethyl)-4-isopropyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 849-(2,3-difluorophenethyl)-4-isopropyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 854-cyclopropyl-9-(2,3-difluorophenethyl)-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 864-cyclopropyl-9-(2,5-difluorophenethyl)-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 87(R)-9-(2,3-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 889-(2,5-difluorophenethyl)-4-ethyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 899-(2,3-difluorophenethyl)-4-ethyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 90 9-(2,5-difluorophenethyl)-4-isopropyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 91(R)-4-cyclopropyl-9-(2,3-difluorophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 92(R)-4-cyclopropyl-9-(2,5-difluorophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 93(R)-4-methyl-9-phenethyl-2-(prop-2-yn-1-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 94(R)-2-(2-hydroxyethyl)-4-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or 95(R)-2-benzyl-4-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one:optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof.

In another very preferred embodiment of the compound according to theinvention according to general formula I′ the compound is selected fromexamples 1 to 10, 12 to 17, 19 to 30, 43, and 55 to 63, optionally inform of one of the stereoisomers, preferably enantiomers ordiastereomers, a racemate or in form of a mixture of at least two of thestereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt thereof.

In another very preferred embodiment of the compound according to theinvention according to general formula I′ the compound is selected fromexamples 1 to 10, 12 to 17, 19 to 30, 43, 55 to 63, 66, 67, and 71 to73; optionally in form of one of the stereoisomers, preferablyenantiomers or diastereomers, a racemate or in form of a mixture of atleast two of the stereoisomers, preferably enantiomers and/ordiastereomers, in any mixing ratio, or a corresponding salt thereof.

In another preferred embodiment of the compound according to theinvention according to general formula I″ the compound is selected fromexamples 11, 18, 31 to 42, and 44 to 53, optionally in form of one ofthe stereoisomers, preferably enantiomers or diastereomers, a racemateor in form of a mixture of at least two of the stereoisomers, preferablyenantiomers and/or diastereomers, in any mixing ratio, or acorresponding salt.

In another preferred embodiment of the compound according to theinvention according to general formula I″ the compound is selected fromexamples 11, 18, 31 to 42, 44 to 53, 70, 74 to 77, 80, 81, 87, 91-94;optionally in form of one of the stereoisomers, preferably enantiomersor diastereomers, a racemate or in form of a mixture of at least two ofthe stereoisomers, preferably enantiomers and/or diastereomers, in anymixing ratio, or a corresponding salt.

As this invention is aimed at providing a compound or a chemicallyrelated series of compounds which act as dual ligands of the σ₁ receptorand the μ-opioid receptor a very preferred embodiment in which thecompounds are selected which act as dual ligands of the σ₁ receptor andthe μ-opioid receptor and especially compounds which have a bindingexpressed as K_(i) which is preferably <1000 nM for both receptors, morepreferably <500 nM, even more preferably <100 nM.

In the following the phrase “compound of the invention” is used. This isto be understood as any compound according to the invention as describedabove according to general formulas I, I′ or I″.

The compounds of the invention represented by the above describedformula (I) may include enantiomers depending on the presence of chiralcentres or isomers depending on the presence of multiple bonds (e.g. Z,E). The single isomers, enantiomers or diastereoisomers and mixturesthereof fall within the scope of the present invention.

In general the processes are described below in the experimental part.The starting materials are commercially available or can be prepared byconventional methods.

As a further general remark, the use of “comprising” and “comprises” asused herein, especially when defining the steps of a process is to beunderstood as also disclosing “consisting of” and “consists of”respectively etc. Thus, this also includes that the steps of therespective process are then to be also understood to be limited to thesteps preceded by this “comprising” or “comprises” etc.

A preferred aspect of the invention is also a process for the productionof a compound according to formula I,

wherein R₁, R₂, R₃ and R_(3′) are as already defined in the descriptionwherein a compound of formula VIIIH or its suitable salt like thehydrochloride

wherein R₁, R₃ and R_(3′) are already defined above in the description,is reacted with a compound according to formula IX, X or XI.

wherein R₂ is as already defined above in the description, and whereinLG is a leaving group, leading to a compound according to formula (I)

A particular embodiment is a process for the preparation of a compoundof general formula I

wherein

-   -   R₁, R₂, R₃ and R_(3′) are as already defined in the description;        which comprises the steps of    -   (a) Reacting a compound of formula V

with a compound of formula VI

wherein W and LG are leaving groups, R₃ and R_(3′) are as alreadydefined in the description;to obtain a compound of formula VII

wherein LG is a leaving group, R₃ and R_(3′) are as already defined inthe description;and

-   -   (b) Carrying out a cyclisation of the resulting compound in a        suitable solvent, in the presence of a strong base and at a        temperature comprised between −78° C. and the reflux        temperature;

Another particular embodiment of the invention is a process for thepreparation of a compound of general formula I′

whereinq is 1, 2, 3 or 4 and R₁ and R₂ are as defined in the description;which comprises the steps of

-   -   (a) reacting a compound of formula V

wherein R₁ and R₂ are as defined in the description;with a compound of formula XX

wherein W and LG are leaving groups, q is as defined in the description;to obtain a compound of formula XXI

wherein W and LG are leaving groups, R₂ and q are as defined in thedescription

-   -   (b) Carrying out a cyclisation of the resulting compound in a        suitable solvent, in the presence of a strong base and at a        temperature comprised between −78° C. and the reflux        temperature; leading to a compound of formula XXII,

-   -   (c) and treating with a strong base such as lithium        diisopropylamide or potassium tert-butoxide, in an aprotic        solvent such as tetrahydrofuran, at a suitable temperature,        preferably cooling.

Preparation of the HCl salt: To a solution of the free base obtained, ina suitable solvent, preferably in anhydrous diethyl ether, HCl wasadded, and the mixture was stirred, preferably at room temperature,preferably for 1 h. The solvent was evaporated, preferably under vacuum,to give the corresponding HCl salt.

The obtained reaction products may, if desired, be purified byconventional methods, such as crystallisation and chromatography. Wherethe above described processes for the preparation of compounds of theinvention give rise to mixtures of stereoisomers, these isomers may beseparated by conventional techniques such as preparative chromatography.If there are chiral centers the compounds may be prepared in racemicform, or individual enantiomers may be prepared either byenantiospecific synthesis or by resolution.

One preferred pharmaceutically acceptable form of a compound of theinvention is the crystalline form, including such form in pharmaceuticalcomposition. In the case of salts and also solvates of the compounds ofthe invention the additional ionic and solvent moieties must also benon-toxic. The compounds of the invention may present differentpolymorphic forms, it is intended that the invention encompasses allsuch forms.

Another aspect of the invention refers to a pharmaceutical compositionwhich comprises a compound according to the invention as described aboveaccording to general formulas I, I′, or I″ or a pharmaceuticallyacceptable salt or stereoisomer thereof, and a pharmaceuticallyacceptable carrier, adjuvant or vehicle. The present invention thusprovides pharmaceutical compositions comprising a compound of thisinvention, or a pharmaceutically acceptable salt or stereoisomersthereof together with a pharmaceutically acceptable carrier, adjuvant,or vehicle, for administration to a patient.

As a general remark, the use of “comprising” and “comprises” as usedherein, especially when defining the contents of a medicament or apharmaceutical formulation is to be understood as also disclosing“consisting of” and “consists of” respectively etc. Thus, this alsoincludes that the contents of the respective medicament orpharmaceutical formulation are then to be also understood to be limitedto the exact contents preceded by this “comprising” or “comprises” etc.

Examples of pharmaceutical compositions include any solid (tablets,pills, capsules, granules etc.) or liquid (solutions, suspensions oremulsions) composition for oral, topical or parenteral administration.

In a preferred embodiment the pharmaceutical compositions are in oralform, either solid or liquid. Suitable dose forms for oraladministration may be tablets, capsules, syrops or solutions and maycontain conventional excipients known in the art such as binding agents,for example syrup, acacia, gelatin, sorbitol, tragacanth, orpolyvinylpyrrolidone; fillers, for example lactose, sugar, maize starch,calcium phosphate, sorbitol or glycine; tabletting lubricants, forexample magnesium stearate; disintegrants, for example starch,polyvinylpyrrolidone, sodium starch glycollate or microcrystallinecellulose; or pharmaceutically acceptable wetting agents such as sodiumlauryl sulfate.

The solid oral compositions may be prepared by conventional methods ofblending, filling or tabletting. Repeated blending operations may beused to distribute the active agent throughout those compositionsemploying large quantities of fillers. Such operations are conventionalin the art. The tablets may for example be prepared by wet or drygranulation and optionally coated according to methods well known innormal pharmaceutical practice, in particular with an enteric coating.

The pharmaceutical compositions may also be adapted for parenteraladministration, such as sterile solutions, suspensions or lyophilizedproducts in the appropriate unit dosage form. Adequate excipients can beused, such as bulking agents, buffering agents or surfactants.

The mentioned formulations will be prepared using standard methods suchas those described or referred to in the Spanish and US Pharmacopoeiasand similar reference texts.

Administration of the compounds or compositions of the present inventionmay be by any suitable method, such as intravenous infusion, oralpreparations, and intraperitoneal and intravenous administration. Oraladministration is preferred because of the convenience for the patientand the chronic character of the diseases to be treated.

Generally an effective administered amount of a compound of theinvention will depend on the relative efficacy of the compound chosen,the severity of the disorder being treated and the weight of thesufferer. However, active compounds will typically be administered onceor more times a day for example 1, 2, 3 or 4 times daily, with typicaltotal daily doses in the range of from 0.1 to 1000 mg/kg/day.

The compounds and compositions of this invention may be used with otherdrugs to provide a combination therapy. The other drugs may form part ofthe same composition, or be provided as a separate composition foradministration at the same time or at different time.

Another aspect of the invention refers to the use of a compound of theinvention or a pharmaceutically acceptable salt or isomer thereof in themanufacture of a medicament.

Another aspect of the invention refers to a compound of the inventionaccording as described above according to general formulas I, I′, or I″or a pharmaceutically acceptable salt or isomer thereof, for use as amedicament for the treatment of pain. Preferably the pain is medium tosevere pain, visceral pain, chronic pain, cancer pain, migraine,inflammatory pain, acute pain or neuropathic pain, allodynia orhyperalgesia. This may include mechanical allodynia or thermalhyperalgesia.

Another aspect of the invention refers to the use of a compound of theinvention in the manufacture of a medicament for the treatment orprophylaxis of pain.

In a preferred embodiment the pain is selected from medium to severepain, visceral pain, chronic pain, cancer pain, migraine, inflammatorypain, acute pain or neuropathic pain, allodynia or hyperalgesia, alsopreferably including mechanical allodynia or thermal hyperalgesia.

Another aspect of this invention relates to a method of treating orpreventing pain which method comprises administering to a patient inneed of such a treatment a therapeutically effective amount of acompound as above defined or a pharmaceutical composition thereof. Amongthe pain syndromes that can be treated are medium to severe pain,visceral pain, chronic pain, cancer pain, migraine, inflammatory pain,acute pain or neuropathic pain, allodynia or hyperalgesia, whereas thiscould also include mechanical allodynia or thermal hyperalgesia.

The present invention is illustrated below with the aid of examples.These illustrations are given solely by way of example and do not limitthe general spirit of the present invention.

Examples General Experimental Part (Methods and Equipment of theSynthesis and Analysis) Scheme 1:

A 4-step process is described for the preparation of compounds ofgeneral formula (I) starting from a ketone of formula II, as shown inthe following scheme:

wherein R₁, R₂, R₃ and R_(3′) have the meanings as defined above for acompound of formula (I), W represents a leaving group such as chloro orbromo, LG represents another leaving group such as halogen, mesylate,tosylate or triflate, P represents a suitable protecting group(preferably Boc) and P′ represents another suitable protecting group(preferably 4-methoxybenzyl).

The 4 step-process is carried out as described below:

Step 1: A compound of formula III is prepared by treating a compound offormula II with a suitable methyl-transfer reagent such astrimethylsulfoxonium iodide or trimethylsulfonium iodide, in a suitableaprotic solvent such as dimethylsulfoxide, and in the presence of astrong base such as sodium hydride or potassium tert-butoxide, at asuitable temperature, preferably comprised between room temperature and60° C.Step 2: A compound of formula V is prepared by reacting a compound offormula III with an amine of formula IV, in a suitable solvent such asan alcohol, preferably ethanol-water mixtures, at a suitable temperaturecomprised between room temperature and the reflux temperature,preferably at room temperature.Step 3: A compound of formula VII is prepared by reacting a compound offormula V with an acylating agent of formula VI. The acylation reactionis carried out in a suitable solvent, such as dichloromethane or ethylacetate-water mixtures; in the presence of an organic base such astriethylamine or diisopropylethylamine or an inorganic base such asK₂CO₃; and at a suitable temperature, preferably comprised between −78°C. and room temperature.Step 4: The intramolecular cyclization of a compound of formula VIIrenders a compound of formula (I). The cyclization reaction is carriedout in a suitable solvent, such as tetrahydrofuran; in the presence of astrong base such as potassium tert-butoxide or sodium hydride; and at asuitable temperature, comprised between −78° C. and room temperature,preferably cooling.

Alternatively, the group CH₂CH₂R₂ can be incorporated in the last stepof the synthesis by reaction of a compound of formula VIIIH with acompound of formula IX, X or XI, as shown in Scheme 1. A compound offormula VIIIH is obtained by deprotection of a compound of formulaVIIIP, wherein P represents a suitable protecting group, preferably Boc(tert-butoxycarbonyl). When the protecting group is Boc, thedeprotection can be conducted by adding a solution of a strong acid suchas HCl, in a suitable solvent such as diethyl ether, 1,4-dioxane ormethanol, or with trifluoroacetic acid in dichloromethane. A compound offormula VIIIP is prepared from a compound of formula IIP following thesame sequence described for the synthesis of compounds of formula (I).

The alkylation reaction between a compound of formula VIIIH (or asuitable salt such as trifluoroacetate or hydrochloride) and a compoundof formula IX is carried out in a suitable solvent, such asacetonitrile, dichloromethane, 1,4-dioxane or dimethylformamide,preferably in acetonitrile; in the presence of an inorganic base such asK₂CO₃ or Cs₂CO₃, or an organic base such as triethylamine ordiisopropylethylamine, preferably K₂CO₃; at a suitable temperaturecomprised between room temperature and the reflux temperature,preferably heating, or alternatively, the reactions can be carried outin a microwave reactor. Additionally, an activating agent such as NaIcan be used.

The reductive amination reaction between a compound of formula VIIIH anda compound of formula X is carried out in the presence of a reductivereagent, preferably sodium triacetoxyborohydride, in an aprotic solvent,preferably tetrahydrofuran or dichloroethane, optionally in the presenceof an acid, preferably acetic acid.

The condensation reaction between a compound of general formula VIIIHand a compound of formula XI is preferably carried out in a suitablesolvent, such as isopropanol, n-butanol or 2-methoxyethanol, optionallyin the presence of an organic base such as triethylamine ordiisopropylethylamine, at a suitable temperature comprised between roomtemperature and the reflux temperature, preferably heating, oralternatively, the reactions can be carried out in a microwave reactor.

In another alternative approach, the R₁ substituent can be incorporatedlater in the sequence by the reaction of a compound of formula XVIIIwith a compound of formula XIX. The alkylation reaction is carried outin an aprotic solvent, preferably dimethylformamide, in the presence ofan inorganic base such as NaH, at a suitable temperature, preferablybetween room temperature and 60° C.

A compound of formula XVIII is synthesized following an analogoussequence as described for the synthesis of compounds of formula I, buteffecting step 2 using ammonia instead of an amine. Alternatively, acompound of formula XVIII can be prepared by reaction of a compound offormula XVIIIH (prepared from a compound of formula XVIIIP, wherein Prepresents a suitable protecting group) with a compound of formula IX, Xor XI, as described above.

Additionally, a compound of formula XVIII can be prepared from acompound of formula XV, wherein P′ represents a suitable protectinggroup, preferably a 4-methoxybenzyl group. The deprotection reaction iscarried out with cerium ammonium nitrate in a suitable solvent such asmixtures of acetonitrile-water or by heating in trifluoroacetic acid orhydrochloric acid.

A compound of formula XV is synthesized from a compound of formula IIIand an amine of formula XII following an analogous sequence as describedfor the synthesis of compounds of formula (I). Alternatively, a compoundof formula XV can be prepared by reaction of a compound of formula XVH(prepared from a compound of formula XVP, wherein P represents asuitable protecting group) with a compound of formula IX, X or XI, asdescribed above.

Alternatively, a compound of formula I can be obtained by resolution ofa racemic mixture either by chiral preparative HPLC or bycrystallization of a diastereomeric salt or co-crystal. The racemiccompound can be prepared following the same synthetic sequencesdescribed for the preparation of a compound of formula I. In addition,the resolution step can be carried out at a previous stage, using anysuitable intermediate.

The compounds of general formula II, IIP, IV, VI, IX, X, XI, XII and XIXwherein R₁, R₂, R₃, R_(3′), LG, V, W, P and P′ have the meanings asdefined above, are commercially available or can be prepared byconventional methods described in the bibliography.

Scheme 2

The compounds of general formula (I) wherein R₃ and R_(3′) takentogether form (with the connecting C-atom) a C₃₋₆ cycloalkyl group(compounds of formula Ia) or R₃ and R_(3′) are equal (compounds offormula Ib) can alternatively be prepared as described in the followingscheme:

wherein R₁, R₂ and R₃ have the meanings as defined above for a compoundof formula (I), q represents 1, 2, 3 or 4, LG represents a leaving groupsuch as halogen, mesylate, tosylate or triflate, W represents anotherleaving group such as chloro or bromo, P represents a suitableprotecting group (preferably Boc) and P′ represents another suitableprotecting group (preferably 4-methoxybenzyl).

A compound of formula Ia can be prepared from a compound of formula XXIIby treatment with a strong base such as lithium diisopropylamide orpotassium tert-butoxide, in an aprotic solvent such as tetrahydrofuran,at a suitable temperature, preferably cooling. A compound of formulaXXII can be synthesized from a compound of formula V and a compound offormula XX following the reaction conditions described in Scheme 1.

Alternatively, a compound of formula Ia can be prepared from a compoundof formula XXVII and a compound of formula XIX following the reactionconditions described in Scheme 1. A compound of formula XXVII can besynthesized from a compound of formula XIII and a compound of formula XXfollowing the reaction conditions described in Scheme 1.

A compound of formula Ib can be prepared from a compound of formulaXXVIII by reacting a compound of formula XXVIII with 2 equivalents of analkylating agent of formula XXX. An analogous double-alkylation processcan be used for the alternative preparation of compounds of formula Ia,by reacting a compound of formula XXVIII with an alkylating agent offormula XXIX. The alkylation reactions are carried out in the presenceof a strong base such as lithium diisopropylamide or potassiumtert-butoxide, in an aprotic solvent such as tetrahydrofuran, at asuitable temperature, preferably comprised between −78° C. and roomtemperature. Compounds of formula XXVIII can be prepared from compoundsof formula V and chloroacetyl chloride (or a suitable analogue) as theacylating agent, following the reaction conditions described in Scheme1.

In addition, the group CH₂CH₂R₂ may be incorporated at different stagesof the synthesis to prepare compounds of formula Ia and Ib from suitableprecursors and compounds of formula IX, X and XI, following similarreaction conditions as described in Scheme 1 for the preparation ofcompounds of formula (I)

The compounds of general formula IX, X, XI, XIX, XX, XXIX and XXXwherein R₁, R₂, R₃, q, LG, W, P and P′ have the meanings as definedabove, are commercially available or can be prepared by conventionalmethods described in the bibliography.

Moreover, certain compounds of the present invention can also beobtained starting from other compounds of formula I by appropriateconversion reactions of functional groups, in one or several steps,using well-known reactions in organic chemistry under standardexperimental conditions. As a way of example, some of these conversionsinclude the demethylation of a methoxy group to yield an hydroxy group,the reduction of a nitro group to yield an amino group, the acylation ofan amino group to yield an acylamino group, the conversion of an aminogroup into an ureido group and the conversion of an ester to an amide.

Examples

All solvents used for synthesis were p. a. quality.

The following abbreviations are used in the examples:

ACN: acetonitrileBoc: tert-butoxycarbonylCAN: cerium ammonium nitrateDCM: dichloromethaneDEA: diethylamineDMF: dimethylformamideDMSO: dimethylsulfoxideEtOH: ethanolEX: exampleh: hour/sHPLC: high performance liquid chromatographyINT: intermediateIPA: isopropanolLDA: lithium diisopropylamideMeOH: methanolMS: mass spectrometryMin.: minutesQuant: quantitativeRet.: retentionr.t.: room temperatureSat: saturateds.m.: starting materialTFA: trifluoroacetic acidTHF: tetrahydrofuranWt: weight

The following method was used to determine the HPLC-MS spectrums:

Column: Xbridge C₁₈ XP 30×4.6 mm, 2.5 μm; Temperature: 40° C.;

Flow: 2.0 mL/min;Gradient: NH₄HCO₃ pH 8: ACN (95:5) - - - 0.5 min - - - (95:5) - - - 6.5min - - - (0:100) - - - 1 min - - - (0:100);Sample dissolved aprox. 1 mg/mL in NH₄HCO₃ pH 8/ACNAlternatively, method B was used in some cases:

Method B: Column: Gemini-NX 30×4.6 mm, 3 um Temperature: 40° C.

Flow: 2.0 mL/minGradient: NH₄HCO₃ pH 8: ACN (95:5) - - - 0.5 min - - - (95:5) - - - 6.5min - - - (0:100) - - - 1 min - - - (0:100)Sample dissolved aprox. 1 mg/mL in NH₄HCO₃ pH 8/ACN

Synthesis of Intermediates Intermediate 1A: tert-butyl1-oxa-6-azaspiro[2.5]octane-6-carboxylate

To a suspension of trimethylsulfoxonium iodide (24.3 g, 110 mmol) andNaH (4.4 g, 60 wt % in mineral oil, 110 mmol) in DMSO (140 mL), asolution of tert-butyl 4-oxopiperidine-1-carboxylate (20.0 g, 100 mmol)in DMSO (140 mL) was added dropwise. The reaction mixture was stirred atr.t. for 30 min, then heated at 50° C. for 1 h. After cooling to r.t.,ice was slowly added, and the reaction mixture was extracted three timeswith ethyl acetate. The organic phases were combined, washed with water,dried over MgSO₄ and concentrated under vacuum to give the titlecompound (17.6 g, 82% yield) as a white solid. HPLC retention time: 3.31min; MS: 158 (M+H−56).

This method was used for the preparation of intermediate 1B usingsuitable starting materials:

Ret time MS INT Structure Chemical name (min) (M + H) 1B

6-phenethyl-1-oxa-6- azaspiro[2.5]octane 3.36 218

Intermediate 2A: tert-butyl4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate

A mixture of intermediate 1A (10.0 g, 46.9 mmol) and ammonia solution(201 mL, 7 M solution in methanol, 1.4 mol) was stirred at r.t.overnight. The solvent was removed under vacuum and the residue waspurified by flash chromatography, silica gel, gradient dichloromethaneto methanol:dichloromethane (1:4) to give the title compound (7.4 g, 69%yield) as a white solid. HPLC retention time: 2.15 min; MS: 131(M+H−100).

Intermediate 2B: tert-butyl4-hydroxy-4-((methylamino)methyl)piperidine-1-carboxylate

To a solution of intermediate 1A (0.50 g, 2.34 mmol) in a mixture ofethanol-water 5.5:1 (14 mL), methylamine (4.1 mL, 40% solution in water,47 mmol) was added. The reaction mixture was stirred at r.t. overnightin a sealed tube. The solvent was removed under vacuum to give the titlecompound (0.534 g, 93% yield) as a white solid. HPLC retention time:2.28 min; MS: 189 (M+H−56).

This method was used for the preparation of intermediates 2C-2G usingsuitable starting materials:

Ret time MS INT Structure Chemical name s.m. (min) (M + H) 2C

tert-butyl 4- ((ethylamino)methyl)- 4-hydroxypiperidine- 1-carboxylate1A 2.35 259 2D

tert-butyl 4-hydroxy- 4-((isopropylamino) methyl)piperidine-1-carboxylate 1A 2.61 273 2E

tert-butyl 4- ((cyclopropylamino) methyl)-4- hydroxypiperidine-1-carboxylate 1A 3.28 271 2F

tert-butyl 4-hydroxy- 4-(((4- methoxybenzyl)amino) methyl)piperidine-1-carboxylate 1A 3.80 351 2G

4-((methylamino) methyl)-1- phenethylpiperidin-4-ol 1B 2.26 249

Intermediate 3A: tert-butyl2-(2-chloroethyl)-4-isopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate

Step 1. tert-butyl4-((2-bromo-4-chloro-N-isopropylbutanamido)methyl)-4-hydroxypiperidine-1-carboxylate:To a solution of intermediate 2D (0.500 g, 1.84 mmol) and triethylamine(0.613 mL, 4.41 mmol) in dichloromethane (95 mL), a solution of2-bromo-4-chlorobutanoyl chloride (prepared as described in U.S. Pat.No. 6,114,541A1 (2000) Ex1) (0.605 g, 2.75 mmol) in dichloromethane (95mL) was added dropwise at 0° C. The reaction mixture was stirred at r.t.for 4 h, NaHCO₃ sat solution was added and the aqueous phase wasextracted with dichloromethane. The organic phases were combined, driedover MgSO₄, filtered and concentrated to dryness. The residue waspurified by flash chromatography, silica gel, gradient dichloromethaneto methanol:dichloromethane (1:4) to give the title compound (0.243 g,29%). HPLC retention time: 4.75 min; MS: 357 (M+H−100).Step 2. Title compound: To a solution of the crude product obtained instep 1 in THF (5 mL), potassium tert-butoxide solution (1.05 mL, 1M inTHF, 1.05 mmol) was added dropwise. The reaction mixture was stirred atr.t. overnight. Water was then added, the phases were separated and theaqueous phase was extracted with ethyl acetate. The organic phases werecombined, dried over MgSO₄, filtered and concentrated under vacuum. Theresidue was purified by flash chromatography, silica gel, gradientdichloromethane to methanol:dichloromethane (1:4) to give the titlecompound (89 mg, 45% yield). HPLC retention time: 4.48 min; MS: 375(M+H).

This method was used for the preparation of intermediate 3B usingsuitable starting materials:

Ret time MS INT Structure Chemical name s.m. (min) (M + H) 3B

tert-butyl 2-(2-chloroethyl)- 4-ethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane-9- carboxylate 2C 4.27 361

Intermediate 3C: (R)-tert-butyl2,4-dimethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate

Step 1. (S)-tert-butyl4-((2-chloro-N-methylpropanamido)methyl)-4-hydroxypiperidine-1-carboxylate:To a solution of intermediate 2B (0.521 g, 2.13 mmol) in ethyl acetate(10 mL), a solution of K₂CO₃ (0.825 g, 5.97 mmol) in water (7 mL) wasadded. After cooling to 0° C., a solution of (S)-2-chloropropanoylchloride (0.368 g, 2.90 mmol) in ethyl acetate (2 mL) was addeddropwise. The reaction mixture was stirred at 0° C. for 30 min, thelayers were separated and the aqueous phase was extracted with ethylacetate. The organic phases were combined, washed with 0.5 M HCl aqueoussolution and then NaHCO₃ sat solution, dried over MgSO₄, filtered andconcentrated to dryness to give the title compound (0.594 g). HPLCretention time: 3.48 min; MS: 235 (M+H−100).Step 2. Title compound: A solution of the crude product obtained in step1 in THF (30 mL) was cooled to −78° C. using a dry ice/acetone bath.After addition of potassium tert-butoxide solution (1.95 mL, 1M in THF,1.95 mmol), the reaction mixture was stirred at −78° C. for 30 min.NH₄Cl sat solution was then added, and the aqueous phase was extractedwith ethyl acetate. The organic phases were combined, dried over MgSO₄,filtered and concentrated under vacuum. The residue was crystallizedfrom hot isopropyl acetate to give the title compound (0.320 g, 60%yield). HPLC retention time: 3.32 min; MS: 299 (M+H). Optical purity:98.9% ee, determined by chiral HPLC: column: Chiralpak ADH 250×4.6 mm,5μ; temperature: 25° C.; flow: 0.5 mL/min; eluent: heptane/(ethanol+0.2%DEA) 85:15.

This method was used for the preparation of intermediates 3D-3O usingsuitable starting materials:

Ret time MS INT Structure Chemical name s.m. (min) (M + H) 3D

(R)-tert-butyl 4-ethyl-2- methyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane-9- carboxylate 2C 3.67 313 3E

(R)-tert-butyl 4-isopropyl-2- methyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane-9- carboxylate 2D 3.94 327 3F

(R)-tert-butyl 4-cyclopropyl- 2-methyl-3-oxo-1-oxaa-4,9-diazaspiro[5.5]undecane-9- carboxylate 2E 3.74 325 3G

(R)-tert-butyl 2-ethyl-4- methyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane-9- carboxylate 2B 3.82 313 3H

(R)-tert-butyl 2-isopropyl-4- methyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane-9- carboxylate 2B 4.28 327 3I

(R)-tert-butyl 2,4-diethyl-3- oxo-1-oxa-4,9- diazaspiro[5.5]undecane-9-carboxylate 2C 3.96 327.2 3J

(R)-tert-butyl 2-ethyl-4- isopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane-9- carboxylate 2D 4.24 341.2 3K

tert-butyl 2-(2-chloroethyl)-4- methyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane-9- carboxylate 2B 3.9  347.1 3L

tert-butyl 4-methyl-3-oxo-1- oxa-4,9- diazaspiro[5.5]undecane-9-carboxylate (1*) 2B 2.95 285.1 3M

tert-butyl 4-ethyl-3-oxo-1- oxa-4,9- diazaspiro[5.5]undecane-9-carboxylate (1*) 2C 3.28 (method B) 299.1 3N

tert-butyl 4-isopropyl-3-oxo- 1-oxa-4,9- diazaspiro[5.5]undecane-9-carboxylate (1*) 2D 3.51 313.2 3O

tert-butyl 4-cyclopropyl-3- oxo-1-oxa-4,9- diazaspiro[5.5]undecane-9-carboxylate (1*) 2E 3.35 (method B) 311.1 (1*) In Step 2, after 15 minat −78° C., the reaction mixture was stirred at −30° C. for 2 h and thenit was quenched and worked-up as usual.

Intermediate 4A: tert-butyl 12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecane-8-carboxylate

A solution of intermediate 3B (2.77 g, 7.68 mmol) in THF (75 mL) wascooled to 0° C. After addition of LDA solution (11.5 mL, 2M inTHF/n-heptane/ethylbenzene, 23.0 mmol), the reaction mixture was stirredat 0° C. for 3 h. NH₄Cl sat solution was then added, and the aqueousphase was extracted with dichloromethane. The organic phase was driedover MgSO₄, filtered and concentrated under vacuum. The residue waspurified by flash chromatography, silica gel, gradient dichloromethaneto methanol:dichloromethane (1:4) to give the title compound (1.53 g,61% yield). HPLC retention time: 3.85 min; MS: 325 (M+H).

This method was used for the preparation of intermediate 4B usingsuitable starting materials:

Ret time MS INT Structure Chemical name s.m. (min) (M + H) 4B

tert-butyl 12-isopropyl-13- oxo-4-oxa-8,12- diazadispiro[2.1.5.3]tridecane-8-carboxylate 3A 4.08 339

Intermediate 4B has alternatively been obtained by the alkylation methoddescribed for the preparation of Intermediate 4F (using 2-bromopropaneinstead of iodomethane as the alkylating agent).

Intermediate 4C: tert-butyl 12-(4-methoxybenzyl)-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecane-8-carboxylate

Step 1. tert-butyl4-((2-bromo-4-chloro-N-(4-methoxybenzyl)butanamido)methyl)-4-hydroxypiperidine-1-carboxylate:To a solution of intermediate 2F (9.94 g, 28.4 mmol) and triethylamine(9.5 mL, 68.1 mmol) in dichloromethane (500 mL), a solution of2-bromo-4-chlorobutanoyl chloride (prepared as described in U.S. Pat.No. 6,114,541 A1 (2000) Ex1) (9.35 g, 20.2 mmol) in dichloromethane (200mL) was added dropwise at 0° C. The reaction mixture was stirred at 0°C. for 3 h. Dichloromethane and NaHCO₃ aqueous sat. solution were addedand the phases were separated. The aqueous phase was extracted withdichloromethane and the organic phases were combined, dried over MgSO₄,filtered and concentrated to dryness, to give the title compound (17.6g, crude product). HPLC retention time: 4.82 min; MS: 435 (M+H−100).Step 2. Title compound: A solution of the crude product obtained in step1 (14.8 g, 27.7 mmol) in THF (185 mL) was cooled under nitrogen to 0° C.After addition of potassium tert-butoxide solution (111 mL, 1M in THF,111 mmol), the reaction mixture was stirred at 0° C. for 2 h. NH₄Cl satsolution was then added, and the aqueous phase was extracted with ethylacetate. The organic phases were combined, dried over MgSO₄, filteredand concentrated under vacuum. The residue was purified by flashchromatography, silica gel, gradient dichloromethane tomethanol:dichloromethane (1:4) to give the title compound (5.51 g, 48%yield for the 2 steps). HPLC retention time: 4.46 min; MS: 417 (M+H).

Intermediate 4D: 8-phenethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one

Step 1. 12-(4-methoxybenzyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one trifluoroacetate. To a solutionof intermediate 4C (1.50 g, 3.6 mmol) in dichloromethane (36 mL),trifluoroacetic acid (2.8 mL, 36.0 mmol) was added, and the reactionmixture was stirred at r.t. for 4 h. The solvent was evaporated todryness to give the title compound as a crude product (2.30 g, 67 wt %,quant yield), that was used in the following step without furtherpurification. HPLC retention time: 2.43 min; MS: 317 (M+H).Step 2. 12-(4-methoxybenzyl)-8-phenethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one. A mixture of the crude productobtained in step 1 (2.30 g, 67 wt %, 3.6 mmol), (2-bromoethyl)benzene(0.802 g, 4.3 mmol) and K₂CO₃ (2.49 g, 18.1 mmol) in acetonitrile (36mL) was heated at 80° C. in a sealed tube overnight. Water was added,and the reaction mixture was extracted with ethyl acetate. The organicphases were combined, dried over MgSO₄, filtered and concentrated todryness. The residue was purified by flash chromatography, silica gel,gradient dichloromethane to methanol:dichloromethane (1:4) to give thetitle compound (1.17 g, 77% yield). HPLC retention time: 4.55 min; MS:421 (M+H).Step 3. Title compound: A mixture of the crude product obtained in step2 (0.170 g, 0.404 mmol) and CAN (0.568 g, 1.21 mmol), acetonitrile (2.5mL) and water (2.5 mL) was stirred at r.t. for 7 h. Na₂CO₃ sat solutionwas added to the reaction mixture and it was extracted with ethylacetate. The organic phases were combined, washed with brine, dried overMgSO₄, filtered and concentrated to dryness. The residue was purified byeluting through an acidic ion exchange resin cartridge (SCX), to givethe title compound (106 mg, 88% yield). HPLC retention time: 3.31 min;MS: 301 (M+H).

Intermediate 4E: tert-butyl 13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecane-8-carboxylate

Step 1. 4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-onetrifluoroacetate: A solution of intermediate 4C (1.78 g, 4.26 mmol) inTFA (20 mL) was stirred in a sealed tube at 80° C. for 4 days. Thereaction mixture was concentrated to dryness and water was added to theresidue. The acidic aqueous phase was washed with ethyl ether, which wasdiscarded. The aqueous layer was evaporated to dryness to give the titlecompound (1.17 g). HPLC retention time: 0.33 min; MS: 197 (M+H).Step 2. Title compound: A mixture of the crude product obtained in step1, di-tert-butyl dicarbonate (1.40 g, 6.40 mmol), 1,4-dioxane (40 mL)and 1M NaOH aqueous solution (10 mL) was stirred at r.t. overnight.Water was added and the resulting mixture was extracted with ethylacetate. The organic phases were combined, dried over MgSO₄, filteredand concentrated to dryness. The residue was purified by flashchromatography, silica gel, gradient dichloromethane tomethanol:dichloromethane (1:4) to give the title compound (0.872 g, 69%yield for the 2 steps). HPLC retention time: 3.29 min; MS: 297 (M+H).

Intermediate 4F: tert-butyl 12-methyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecane-8-carboxylate

To a solution of intermediate 4E (0.190 g, 0.641 mmol) in dry DMF (5mL), NaH (51 mg, 60 wt % in mineral oil, 1.28 mmol) was added at r.t.The reaction mixture was stirred at r.t. for 30 min, then iodomethane(0.040 mL, 0.641 mmol) was added and the resulting mixture was stirredat r.t. overnight. Water was added to the reaction mixture and it wasextracted with ethyl acetate. The organic phases were combined, driedover MgSO₄, filtered and concentrated to dryness. The residue waspurified by flash chromatography, silica gel, gradient dichloromethaneto methanol:dichloromethane (1:4) to give the title compound (166 mg,83% yield). HPLC retention time: 3.57 min; MS: 311 (M+H).

Intermediate 5A: tert-butyl2,2-diethyl-4-methyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate

A solution of intermediate 3L (0.200 g, 0.70 mmol) in dry THF (1 mL) wascooled to 0° C. After slow addition of LDA solution (1.41 mL, 2M inTHF/n-heptane/ethylbenzene, 2.81 mmol), the reaction mixture was stirredat 0° C. for 30 min. Iodoethane (0.28 mL, 3.52 mmol) was then added andthe reaction mixture was stirred at 0-5° C. for further 90 min. NH₄Clsat solution was then added, and the aqueous phase was extracted threetimes with ethyl acetate. The combined organic phases were dried overNa₂SO₄, filtered and concentrated under vacuum. The residue was purifiedby flash chromatography, silica gel, gradient dichloromethane tomethanol:dichloromethane (1:4) to give the title compound (186 mg, 78%yield). HPLC retention time: 4.29 min; MS: 341 (M+H).

This method was used for the preparation of intermediates 5B-5D usingsuitable starting materials:

Ret time MS INT Structure Chemical name s.m. (min) (M + H) 5B

tert-butyl 4-ethyl-2,2- dimethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane- 9-carboxylate 3M 3.93 (method B) 327.2 5C

tert-butyl 4-isopropyl-2,2- dimethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane- 9-carboxylate 3N 4.22 (method B) 341.2 5D

tert-butyl 4-cyclopropyl- 2,2-dimethyl-3-oxo-1-oxa- 4,9-diazaspiro[5.5]undecane- 9-carboxylate 3O 4.01 (method B) 339.2

Intermediate 5E: tert-butyl4-methyl-3-oxo-2-(prop-2-yn-1-yl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate

A solution of intermediate 3L (0.500 g, 1.76 mmol) in dry THF (2.5 mL)was cooled to 0° C. After slow addition of LDA solution (1.05 mL, 2M inTHF/n-heptane/ethylbenzene, 2.11 mmol), the reaction mixture was stirredat 0° C. for 30 min. Propargyl bromide solution (0.24 mL, 80% wt intoluene, 2.11 mmol) was then added and the reaction mixture was stirredat 0-5° C. for further 2 h. NH₄Cl sat solution was added and the aqueousphase was extracted three times with dichloromethane. The combinedorganic phases were dried over MgSO₄, filtered and concentrated undervacuum. The residue was purified by flash chromatography, silica gel,gradient dichloromethane to methanol:dichloromethane (1:4) to give thetitle compound (327 mg, 58% yield). HPLC retention time: 3.45 min; MS:323 (M+H).

Intermediate 5F: tert-butyl14-methyl-15-oxo-6-oxa-10,14-diazadispiro[4.1.5.3]pentadecane-10-carboxylate

Step 1. tert-butyl2-(4-bromobutyl)-4-methyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate:A solution of intermediate 3L (0.400 g, 1.41 mmol) in dry THF (20 mL)was cooled to −50° C. After slow addition of LDA solution (2.11 mL, 2Min THF/n-heptane/ethylbenzene, 4.22 mmol), the reaction mixture wasstirred at −50° C. for 30 min. 1,4-Dibromobutane (0.25 mL, 2.11 mmol)was then added and the reaction mixture was stirred at −50° C. forfurther 90 min and then it was allowed to reach room temperature andstirred for an additional hour. NH₄Cl sat solution was added and theaqueous phase was extracted three times with ethyl acetate. The combinedorganic phases were dried over MgSO₄, filtered and concentrated undervacuum to give the title compound as a crude product, that was used assuch without further purification. HPLC retention time: 4.39 min; MS:421 (M+H).Step 2. Title compound: A solution of the product obtained in Step 1(1.41 mmol) in dry THF (30 mL) was cooled to −50° C. After slow additionof LDA solution (2.11 mL, 2M in THF/n-heptane/ethylbenzene, 4.22 mmol),the reaction mixture was stirred at 0° C. for 1 h and then it wasfurther stirred at room temperature for 1 h. NH₄Cl sat solution wasadded and the aqueous phase was extracted with ethyl acetate. Theorganic phase was dried over MgSO₄, filtered and concentrated undervacuum. The residue was purified by flash chromatography, silica gel,gradient dichloromethane to methanol:dichloromethane (1:4) to give thetitle compound (199 mg, 42% yield for the two steps). HPLC retentiontime: 4.09 min; MS: 339 (M+H).

Intermediate 6: tert-butyl2-(2-hydroxyethyl)-4-methyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate

A solution of intermediate 3K (0.200 g, 0.58 mmol) in THF (1 mL) and 1MNaOH solution (1 mL) was heated to reflux in a sealed tube overnight. Itwas then concentrated to dryness and water and ethyl acetate were addedto the residue. The phases were separated and the aqueous phase wasextracted three times with ethyl acetate. The combined organic phaseswere dried over MgSO₄, filtered and concentrated under vacuum to givethe title compound (66 mg, 35% yield). HPLC retention time: 2.96 min;MS: 329 (M+H).

SYNTHESIS OF EXAMPLES Example 1:12-ethyl-8-{2-[3-(trifluoromethyl)pyridin-2-yl]ethyl}-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one hydrochloride

Step 1. 12-ethyl-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-onetrifluoroacetate. To a solution of intermediate 4A (1.50 g, 4.65 mmol)in dichloromethane (46 mL), trifluoroacetic acid (3.6 mL, 46.5 mmol) wasadded, and the reaction mixture was stirred at r.t. for 3 h. The solventwas evaporated to dryness to give the title compound as a crude product(3.02 g, 52 wt %, quant yield), that was used in the following stepwithout further purification. HPLC retention time: 0.83 min; MS: 225(M+H).Step 2. 12-ethyl-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one. Thecrude product obtained in step 1 (208 mg, 52 wt %, 0.331 mmol) wasdissolved in dichloromethane and washed twice with 1M NaOH aqueoussolution. The combined aqueous phases were extracted withdichloromethane and the organic phases were combined, washed with water,dried over MgSO₄, filtered and concentrated under vacuum to give thetitle compound as a crude product (0.056 g, 78%). HPLC retention time:0.75 min; MS: 225 (M+H).Step 3. 12-ethyl-8-{2-[3-(trifluoromethyl)pyridin-2-yl]ethyl}-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one: A solution of the crude productobtained in step 2 (0.056 g, 0.249 mmol) and3-trifluoromethyl-2-vinylpyridine (prepared similarly as described inAngew. Chem. Int. Ed., 2013, 52, 9755) (0.068 g, 0.393 mmol) in2-methoxyethanol (0.6 mL) was heated at 120° C. in a sealed tube underargon for 1 day. The reaction mixture was allowed to cool to r.t. andthe solvent was evaporated. The residue was purified by flashchromatography, silica gel, gradient dichloromethane tomethanol:dichloromethane (1:4) to give the title compound as its freebase (45 mg, 45% yield). HPLC retention time: 3.49 min; MS: 398.0 (M+H).Step 4. Title compound: To a solution of the free base obtained in Step3 (45 mg, 0.113 mmol) in anhydrous diethyl ether (2 mL), HCl (2Msolution in diethyl ether, 0.056 mL, 0.113 mmol) was added, and themixture was stirred at r.t. for 1 h. The solvent was evaporated undervacuum to give the corresponding HCl salt (45 mg, 92% yield). HPLCretention time: 3.62 min; MS: 398.0 (M+H).

This method was used for the preparation of examples 2-6 using suitablestarting materials:

Ret time MS EX Structure Chemical name (min) (M + H) 2

12-ethyl-8-{2-[6- (trifluoromethyl)pyridin-2- yl]ethyl}-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan- 13-one hydrochloride 3.76 398.0 3

12-ethyl-8-[2-(3- fluoropyridin-2-yl)ethyl]-4- oxa-8,12-diazadispiro[2.1.5.3]tridecan- 13-one hydrochloride 3.05 348.1 4

12-ethyl-8-{2-[4- (trifluoromethyl)pyridin-2- yl]ethyl}-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan- 13-one hydrochloride 3.65 398.2 5

8-[2-(3-chloropyridin-2- yl)ethyl]-12-ethyl-4-oxa- 8,12-diazadispiro[2.1.5.3]tridecan- 13-one hydrochloride 3.29 364.1 6

8-[2-(6-aminopyridin-2- yl)ethyl]-12-ethyl-4-oxa- 8,12-diazadispiro[2.1.5.3]tridecan- 13-one 2.73 345.2

Where indicated, the hydrochloride salts were prepared as described inexample 1

Example 7: 12-ethyl-8-phenethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one hydrochloride

A mixture of the crude product obtained in step 1 of example 1 (0.044 g,0.129 mmol), (2-bromoethyl)benzene (0.021 mL, 0.155 mmol), sodium iodide(0.012 g, 0.078 mmol) and K₂CO₃ (0.143 g, 1.04 mmol) in acetonitrile (2mL) was heated at 80° C. in a sealed tube overnight. Water was added,and the reaction mixture was extracted with ethyl acetate. The organicphases were combined, washed with brine, dried over MgSO₄, filtered andconcentrated to dryness. The residue was purified by flashchromatography, silica gel, gradient dichloromethane tomethanol:dichloromethane (1:4) to give the title compound as its freebase (12 mg, 28% yield).

The previous compound was converted to its hydrochloride salt asdescribed in example 1. HPLC retention time: 3.74 min; MS: 329.1 (M+H).

This method was used for the preparation of examples 8-53 using suitablestarting materials:

Ret time MS EX Structure Chemical name (min) (M + H) 8

12-isopropyl-8-phenethyl-4- oxa-8,12- diazadispiro[2.1.5.3]tridecan-13-one 4.10 343.2 9

12-isopropyl-8-[2-(pyridin-2- yl)ethyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan- 13-one dihydrochloride 3.00 344.2 10

12-ethyl-8-[2-(pyridin-2- yl)ethyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan- 13-one hydrochloride 2.76 330 11

(R)-2,4-dimethyl-9- phenethyl-1-oxa-4,9- diazaspiro[5.5]undecan-3- onehydrochloride (*1) 3.35 303.2 12

12-ethyl-8-{2-[6- (trifluoromethyl)pyridin-3- yl]ethyl}-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan- 13-one hydrochloride 3.71 398 13

12-ethyl-8-[2-(6- methoxypyridin-2-yl)ethyl]-4- oxa-8,12-diazadispiro[2.1.5.3]tridecan- 13-one hydrochloride 3.43 360.1 14

12-ethyl-8-[2-(6- hydroxypyridin-2-yl)ethyl]-4- oxa-8,12-diazadispiro[2.1.5.3]tridecan- 13-one hydrochloride (4*) 2.54 346 15

4-(2-{12-ethyl-13-oxo-4-oxa- 8,12- diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)benzene-1- sulfonamide 2.80 408 16

4-(2-{12-ethyl-13-oxo-4-oxa- 8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)-N- methylbenzene-1- sulfonamide 3.13 422 17

12-ethyl-8-{2-[3- (trifluoromethoxy)phenyl]ethyl}- 4-oxa-8,12-diazadispiro[2.1.5.3]tridecan- 13-one hydrochloride 4.59 413 18

(R)-4-ethyl-2-methyl-9- phenethyl-1-oxa-4,9- diazaspiro[5.5]undecan-3-one hydrochloride (2*) 3.56 317 19

12-ethyl-8-(3-nitrophenethyl)- 4-oxa-8,12-diazadispiro[2.1.5.3]tridecan- 13-one 3.61 374 20

12-ethyl-8-(3- methoxyphenethyl)-4-oxa- 8,12-diazadispiro[2.1.5.3]tridecan- 13-one 3.66 359.1 21

tert-butyl (4-(2-(12-ethyl-13- oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan- 8-yl)ethyl)thiazol-2- yl)carbamate 3.80451.1 22

methyl 4-(2-{12-ethyl-13-oxo- 4-oxa-8,12- diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)benzoate 3.73 387.1 23

12-ethyl-8-[2-(pyridin-4- yl)ethyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan- 13-one 2.74 330.2 24

12-ethyl-8-[2-(pyridin-3- yl)ethyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan- 13-one 2.77 330.2 25

12-ethyl-8-(4- methoxyphenethyl)-4-oxa- 8,12-diazadispiro[2.1.5.3]tridecan- 13-one 3.69 359.2 26

12-ethyl-8-(2- methoxyphenethyl)-4-oxa- 8,12-diazadispiro[2.1.5.3]tridecan- 13-one 3.83 359.2 27

3-(2-{12-ethyl-13-oxo-4-oxa- 8,12- diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)benzonitrile hydrochloride 3.50 354.2 28

4-(2-{12-ethyl-13-oxo-4-oxa- 8,12- diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)-N,N- dimethylbenzamide hydrochloride 3.06 400.2 29

8-[2-fluorophenethyl]-12- methyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan- 13-one hydrochloride 3.72 333.1 30

8-[2-fluorophenethyl]-12- isopropyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan- 13-one hydrochloride 4.22 361.2 31

(R)-2-isorpopyl-4-methyl-9- phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3- one hydrochloride 4.20 331.2 32

(R)-4-ethyl-9-(2- fluorophenethyl)-2-methyl-1- oxa-4,9-diazaspiro[5.5]undecan-3- one hydrochloride 3.78 335.2 33

(R)-2-ethyl-4-methyl-9- phenethyl-1-oxa-4,9- diazaspiro[5.5]undecan-3-one hydrochloride 3.77 317.2 34

(R)-9-(3-fluorophenethyl)-4- isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan- 3-one hydrochloride 3.99 349.2 35

(R)-4-cyclopropyl-9-(2- fluorophenethyl)-2-methyl-1- oxa-4,9-diazaspiro[5.5]undecan-3- one hydrochloride 3.81 347.2 36

(R)-4-isopropyl-2-methyl-9- phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3- one hydrochloride (3*) 3.86 331 37

(R)-9-(2-fluorophenethyl)- 2,4-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3- one hydrochloride 3.53 321.1 38

(R)-9-(3-fluorophenethyl)- 2,4-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3- one hydrochloride 3.54 321.1 39

(R)-9-(2-fluorophenethyl)-4- isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan- 3-one hydrochloride 4.03 349.2 40

(R)-4-cyclopropyl-2-methyl- 9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3- one hydrochloride 3.70 329.2 41

(R)-4-cyclopropyl-9-(3- fluorophenethyl)-2-methyl-1- oxa-4,9-diazaspiro[5.5]undecan-3- one hydrochloride 3.85 347.2 42

(R)-4-ethyl-9-(3- fluorophenethyl)-2-methyl-1- oxa-4,9-diazaspiro[5.5]undecan-3- one hydrochloride 3.80 335.2 43

8-(3-fluorophenethyl)-12- isopropyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan- 13-one hydrochloride 4.25 361.2 44

(R)-2,4-dimethyl-9-(3- (trifluoromethyl)phenethyl)-1- oxa-4,9-diazaspiro[5.5]undecan-3- one hydrochloride 3.98 371.2 45

(R)-2,4-dimethyl-9-(2- (trifluoromethoxy)phenethyl)- 1-oxa-4,9-diazaspiro[5.5]undecan-3- one hydrochloride 4.15 387.1 46

(R)-9-(2-fluorophenethyl)-2- isopropyl-4-methyl-1-oxa-4,9-diazaspiro[5.5]undecan- 3-one hydrochloride 4.25 349.2 47

(R)-9-(3-fluorophenethyl)-2- isopropyl-4-methyl-1-oxa-4,9-diazaspiro[5.5]undecan- 3-one hydrochloride 4.25 349.2 48

(R)-2,4-dimethyl-9-(2- (trifluoromethyl)phenethyl)-1- oxa-4,9-diazaspiro[5.5]undecan-3- one hydrochloride 3.93 371.2 49

(R)-9-(2,6-difluorophenethyl)- 4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan- 3-one hydrochloride 4.06 367.2 50

(R)-9-(2,5-difluorophenethyl)- 4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan- 3-one hydrochloride 4.02 367.2 51

(R)-9-(2,3-difluorophenethyl)- 4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan- 3-one hydrochloride 4.03 367.2 52

(R)-2-ethyl-9-(2- fluorophenethyl)-4-methyl-1- oxa-4,9-diazaspiro[5.5]undecan-3- one hydrochloride 3.75 335.2 53

(R)-2-ethyl-9-(3- fluorophenethyl)-4-methyl-1- oxa-4,9-diazaspiro[5.5]undecan-3- one hydrochloride 3.75 335.2 Where indicated,the hydrochloride salts were prepared as described in example 1 1*.Alternatively prepared by chiral preparative HPLC separation of theracemic compound. Conditions: Column: OJ; Temperature: ambient; Flow:0.8 mL/min; Mobile phase: n-Heptane/IPA 95/5 v/v 2*. Alternativelyprepared by chiral preparative HPLC separation of the racemic compound.Conditions: Column: OJ; Temperature: ambient; Flow: 0.8 mL/min; Mobilephase: n-Heptane/EtOH 95/5 v/v 3*. Alternatively prepared by chiralpreparative HPLC separation of the racemic compound. Conditions: Column:Chiralpak IA; Temperature: ambient; Flow: 0.4 mL/min; Mobile phase:n-Heptane/EtOH 98/2 v/v 4*. Compound obtained as by-product of previousexample

Alternative Method for the Synthesis of Example 11

Step 1.((S)-2-chloro-N-((4-hydroxy-1-phenethylpiperidin-4-yl)methyl)-N-methylpropanamide.To a solution of intermediate 2G (0.500 g, 79 wt %, 1.59 mmol) in ethylacetate (8 mL), a solution of K₂CO₃ (0.779 g, 5.64 mmol) in water (7 mL)was added. After cooling to 0° C., a solution of (S)-2-chloropropanoylchloride (0.31 g, 2.42 mmol) in ethyl acetate (1 mL) was added dropwiseand the reaction mixture was stirred at 0° C. for 30 min. NaHCO₃ satsolution was then added, the layers were separated and the aqueous phasewas extracted with ethyl acetate. The organic phases were combined,dried over MgSO₄, filtered and concentrated to dryness to give the titlecompound (0.500 g, 91% yield). HPLC retention time: 3.13 min; MS: 339(M+H).Step 2. Title compound: A solution of the crude product obtained in step1 in THF (15 mL) was cooled to −78° C. using a dry ice/acetone bath.After addition of potassium tert-butoxide solution (1.62 mL, 1M in THF,1.62 mmol), the reaction mixture was stirred at −78° C. for 30 min.NH₄Cl sat solution was then added and the aqueous phase was extractedwith ethyl acetate. The organic phases were combined, dried over MgSO₄,filtered and concentrated under vacuum to give the title compound (0.400g, 90% yield). HPLC retention time: 3.30 min; MS: 303 (M+H). Opticalpurity: 93.5% ee, determined by chiral HPLC: Column: OJ 250×4.6 mm, 10μ;temperature: 25° C.; flow: 0.5 mL/min; eluent: heptane/ethanol 90:10.

The previous compound was converted to its hydrochloride salt asdescribed in example 1.

This method was used for the preparation of example 54 using suitablestarting materials:

Ret time MS EX Structure Chemical name (min) (M + H) 54

2,2,4-trimethyl-9-phenethyl- 1-oxa-4,9- diazaspiro[5.5]undecan-3- onehydrochloride 3.48 317.2

Example 55: 12-methyl-8-phenethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one hydrochloride

To a solution of intermediate 4D (0.106 g, 0.353 mmol) in dry DMF (3.5mL), NaH (16 mg, 60 wt % in mineral oil, 0.233 mmol) was added. Thereaction mixture was stirred at r.t. for 30 min, then iodomethane (0.024mL, 0.388 mmol) was added and the resulting mixture was stirred at r.t.overnight. Water was added to the reaction mixture and it was extractedwith dichloromethane. The organic phases were combined, washed withbrine, dried over MgSO₄, filtered and concentrated to dryness. Theresidue was purified by flash chromatography, silica gel, gradientdichloromethane to methanol:dichloromethane (1:4) to give the titlecompound as its free base (25 mg, 23% yield).

The previous compound was converted to its hydrochloride salt asdescribed in example 1.

HPLC retention time: 3.53 min; MS: 315.1 (M+H).

Example 56: 8-(3-aminophenethyl)-12-ethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one

A mixture of example 19 (0.139 g, 0.372 mmol) and palladium (14 mg, 10%wt on charcoal) in methanol (3 mL) was stirred at r.t. under 4 bars ofH₂ overnight. Then, the solids were filtered off, and the solvent wasremoved under vacuum to give the title compound (0.129 g, quant. yield).HPLC retention time: 2.98 min; MS: 344.1 (M+H).

Example 57: N-[3-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)phenyl]acetamide

To a solution of example 56 (0.060 g, 0.175 mmol) and triethylamine(0.036 mL, 0.262 mmol) in dichloromethane (1.8 mL), acetyl chloride(0.014 mL, 0.192 mmol) was added dropwise at 0° C. The reaction mixturewas stirred at r.t. overnight. Water was added and the aqueous phase waswashed with dichloromethane, basified with 1M NaOH aqueous solution andextracted with dichloromethane. The organic phases were combined, driedover MgSO₄, filtered and concentrated to dryness. The residue waspurified by eluting through an acidic ion exchange resin cartridge(SCX), to give the title compound (0.048 g, 72% yield). HPLC retentiontime: 3.00 min; MS: 386.1 (M+H).

Example 58: [3-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)phenyl]urea

To a solution of example 56 (0.060 g, 0.175 mmol) in a mixture of aceticacid:water 1:1.5 (1 mL), potassium cyanate (0.021 g, 0.262 mmol) wasadded, and the reaction mixture was stirred at r.t. overnight. NaHCO₃aqueous sat solution was added, and the aqueous phase was washed withdichloromethane, basified with 1M NaOH aqueous solution and extractedwith dichloromethane. The organic phases were combined, dried overMgSO₄, filtered and concentrated under vacuum. The residue was purifiedby eluting through an acidic ion exchange resin cartridge (SCX) to givethe title compound (0.031 g, 46% yield). HPLC retention time: 2.79 min;MS: 387.1 (M+H).

Example 59: 4-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)-N-methylbenzamidehydrochloride

A mixture of example 22 (0.054 g, 0.140 mmol) and methylamine solution(1 mL, 33% in ethanol, 8.1 mmol) was heated at 100° C. in a sealed tubeovernight. It was then concentrated to dryness and the residue waspurified by flash chromatography, silica gel, gradient dichloromethaneto methanol:dichloromethane (1:4) to give the title compound as its freebase (0.021 g, 39% yield).

The previous compound was converted to its hydrochloride salt asdescribed in example 1.

HPLC retention time: 2.81 min; MS: 386.2 (M+H).

Example 60: 12-ethyl-8-(2-hydroxyphenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one

To a solution of example 26 (0.078 g, 0.217 mmol) in dichloromethane (2mL), boron tribromide solution (0.65 mL, 1M in dichloromethane, 0.65mmol) was added dropwise at −78° C. The reaction mixture was allowed towarm to r.t. over a period of 2 h. Then, 1 M NaOH aqueous solution wasadded until pH 8-9 and it was extracted with dichloromethane. Theorganic phases were combined, washed with brine, dried over MgSO₄,filtered and concentrated to dryness. The residue was purified by flashchromatography, silica gel, gradient dichloromethane tomethanol:dichloromethane (1:4) to give the title compound (0.032 g, 43%yield). HPLC retention time: 3.71 min; MS: 345.2 (M+H).

This method was used for the preparation of examples 61-62 starting fromthe corresponding examples described above:

Ret time MS EX Structure Chemical name (min) (M + H) 61

12-ethyl-8-(3- hydroxyphenethyl)-4-oxa- 8,12-diazadispiro[2.1.5.3]tridecan-13-one 3.05 345.1 62

12-ethyl-8-(4- hydroxyphenethyl)-4-oxa- 8,12-diazadispiro[2.1.5.3]tridecan-13-one hydrochloride 2.92 345.2

Where indicated, the hydrochloride salts were prepared as described inexample 1.

Example 63: 8-[2-(2-aminothiazol-4-yl)ethyl]-12-ethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one

To a solution of example 21 (0.070 g, 0.155 mmol) in dichloromethane(2.2 mL), trifluoroacetic acid (0.60 mL, 7.78 mmol) was added. Thereaction mixture was stirred at r.t. overnight. Then, NaHCO₃ satsolution was added. The organic phase was separated and it was washedwith water. The combined aqueous phases were back extracted withdichloromethane. The organic phases were combined, dried over MgSO₄,filtered and concentrated to dryness. The residue was purified by flashchromatography, C₁₈, gradient aqueous NH₄HCO₃ (pH 8) to acetonitrile togive the title compound (0.015 g, 28% yield). HPLC retention time: 2.60min; MS: 351.2 (M+H).

Examples 64 to 94 were prepared according to the procedure described inExample 7, using suitable starting materials:

Ret time MS EX Structure Chemical name (min) (M + H) 64

2,2-diethyl-4-methyl-9- phenethyl-1-oxa-4.9- diazaspiro[5.5]undecan-3-one 4.19 345.2 65

4-cyclopropyl-9-(2- fluorophenethyl)-2,2- dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3- one 4.06 (method B) 361.2 66

8-(2,5-difluorophenethyl)- 12-isopropyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan- 13-one 4.28 379.2 67

8-(2,3-difluorophenethyl)- 12-isopropyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan- 13-one 4.26 379.2 68

10-(2-fluorophenethyl)-14- methyl-6-oxa-10,14- diazadispiro[4.1.5.3]pentadecan-15-one 4.19 361.2 69

10-(3-fluorophenethyl)-14- methyl-6-oxa-10,14- diazadispiro[4.1.5.3]pentadecan-15-one 4.18 361.2 70

(R)-9-(2,5- difluorophenethyl)-4-ethyl-2- methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3- one 3.77 353.1 71

8-(2,5-difluorophenethyl)- 12-ethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan- 13-one 4   365.2 72

12-ethyl-8-(3- fluorophenethyl)-4-oxa- 8,12-diazadispiro[2.1.5.3]tridecan- 13-one 3.87 347.2 73

12-ethyl-8-(2- fluorophenethyl)-4-oxa- 8,12-diazadispiro[2.1.5.3]tridecan- 13-one 3.88 347.2 74

(R)-9-(2,3- difluorophenethyl)-2,4- dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3- one 3.56 339.1 75

(R)-2,4-diethyl-9-(2- fluorophenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3- one 4.07 349.2 76

(R)-2,4-diethyl-9-(3- fluorophenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3- one 4.07 349.2 77

(R)-2-ethyl-9-(3- fluorophenethyl)-4- isopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3- one 4.31 363.2 78

4-ethyl-9-(3- fluorophenethyl)-2,2- dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3- one 3.9  349.2 79

4-ethyl-9-(2- fluorophenethyl)-2,2- dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3- one 3.91 349.2 80

(R)-2-ethyl-9-(2- fluorophenethyl)-4- isopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3- one 4.2  363.2 81

(R)-9-(2,5- difluorophenethyl)-2,4- dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3- one 3.46 339.1 82

9-(3-fluorophenethyl)-4- isopropyl-2,2-dimethyl-1- oxa-4,9-diazaspiro[5.5]undecan-3- one 4.09 407.2 83

9-(2-fluorophenethyl)-4- isopropyl-2,2-dimethyl-1- oxa-4,9-diazaspiro[5.5]undecan-3- one 4.1  363.2 84

9-(2,3-difluorophenethyl)-4- isopropyl-2,2-dimethyl-1- oxa-4,9-diazaspiro[5.5]undecan-3- one 4.42 (method B) 381.2 85

4-cyclopropyl-9-(2,3- difluorophenethyl)-2,2- dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3- one 4.19 (method B) 379.2 86

4-cyclopropyl-9-(2,5- difluorophenethyl)-2,2- dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3- one 4.20 (method B) 379.2 87

(R)-9-(2,3- difluorophenethyl)-4-ethyl-2- methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3- one 3.83 (method B) 353.2 88

9-(2,5-difluorophenethyl)-4- ethyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan- 3-one 4.12 (method B) 367.2 89

9-(2,3-difluorophenethyl)-4- ethyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan- 3-one 4.13 (method B) 367.2 90

9-(2,5-difluorophenethyl)-4- isopropyl-2,2-dimethyl-1- oxa-4,9-diazaspiro[5.5]undecan-3- one 4.39 (method B) 381.2 91

(R)-4-cyclopropyl-9-(2,3- difluorophenethyl)-2-methyl- 1-oxa-4,9-diazaspiro[5.5]undecan-3- one 3.90 (method B) 365.1 92

(R)-4-cyclopropyl-9-(2,5- difluorophenethyl)-2-methyl- 1-oxa-4,9-diazaspiro[5.5]undecan-3- one 3.89 (method B) 365.2 93

(R)-4-methyl-9-phenethyl-2- (prop-2-yn-1-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-3- one (1*) 3.47 327.2 94

(R)-2-(2-hydroxyethyl)-4- methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan- 3-one (2*) 2.74 333.2 1*. Obtained by chiralpreparative HPLC resolution of the racemic compound. Conditions: Column:AS-H; Temperature: ambient; Flow: 15 mL/min; Mobile phase:n-Heptane/(EtOH + 0.33% DEA) 85/15 v/v 2*. Obtained by chiralpreparative HPLC resolution of the racemic compound. Conditions: Column:AS-H; Temperature: ambient; Flow: 10 mL/min; Mobile phase:n-Heptane/(IPA + 0.33% DEA) 70/30 v/v

Example 95:(R)-2-benzyl-4-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one

The alternative method described for the synthesis of Example 11 wasapplied with some minor modifications to prepare the racemic precursor.In Step 1, cinnamoyl chloride was used as acylating agent, and in Step 2the reaction mixture was heated to 80° C. instead of being kept at −78°C. to achieve cyclization. The title compound was obtained after chiralpreparative HPLC separation. Conditions: Column: OJ; Temperature:ambient; Flow: 15 mL/min; Mobile phase: n-Heptane/(EtOH+0.33% DEA) 70/30v/v

HPLC retention time: 4.36 min; MS: 379.2 (M+H).

Table of Examples with Binding to the μ-Opioid Receptor and theσ₁-Receptor:

Biological Activity Pharmacological Study Human σ₁ Receptor RadioligandAssay

To investigate binding properties of test compounds to human 6σ₁receptor, transfected HEK-293 membranes and [³H](+)-pentazocine (PerkinElmer, NET-1056), as the radioligand, were used. The assay was carriedout with 7 μg of membrane suspension, 5 nM of [³H](+)-pentazocine ineither absence or presence of either buffer or 10 μM Haloperidol fortotal and non-specific binding, respectively. Binding buffer containedTris-HCl 50 mM at pH 8. Plates were incubated at 37° C. for 120 minutes.After the incubation period, the reaction mix was then transferred toMultiScreen HTS, FC plates (Millipore), filtered and plates were washed3 times with ice-cold 10 mM Tris-HCL (pH7.4). Filters were dried andcounted at approximately 40% efficiency in a MicroBeta scintillationcounter (Perkin-Elmer) using EcoScint liquid scintillation cocktail

Human μ-Opioid Receptor Radioligand Assay

To investigate binding properties of test compounds to human μ-opioidreceptor, transfected CHO-K1 cell membranes and [³H]-DAMGO (PerkinElmer, ES-542-C), as the radioligand, were used. The assay was carriedout with 20 μg of membrane suspension, 1 nM of [³H]-DAMGO in eitherabsence or presence of either buffer or 10 μM Naloxone for total andnon-specific binding, respectively. Binding buffer contained Tris-HCl 50mM, MgCl2 5 mM at pH 7.4. Plates were incubated at 27° C. for 60minutes. After the incubation period, the reaction mix was thentransferred to MultiScreen HTS, FC plates (Millipore), filtered andplates were washed 3 times with ice-cold 10 mM Tris-HCL (pH 7.4).Filters were dried and counted at approximately 40% efficiency in aMicroBeta scintillation counter (Perkin-Elmer) using EcoScint liquidscintillation cocktail.

Results:

As this invention is aimed at providing a compound or a chemicallyrelated series of compounds which act as dual ligands of the σ₁ receptorand the μ-opioid receptor it is a very preferred embodiment in which thecompounds are selected which act as dual ligands of the σ₁ receptor andthe μ-opioid receptor and especially compounds which have a bindingexpressed as K_(i), which is preferably <1000 nM for both receptors,more preferably <500 nM, even more preferably <100 nM.

The following scale as been adopted for representing the binding to theσ1 receptor and the μ-opioid receptor expressed as K_(i):

-   -   + Both K_(i)-μ and K_(i)-σ₁>=500 nM    -   ++ One K_(i)<500 nM while the other K_(i) is >=500 nM    -   +++ Both K_(i)-μ and K_(i)-σ₁<500 nM    -   ++++ Both K_(i)-μ and K_(i)-σ₁<100 nM

All compounds prepared in the present application exhibit binding to theσ₁ receptor and the μ-opioid receptor, in particular the followingbinding results are shown:

μ and σ₁ dual Ex binding 1 + 2 + 3 ++ 4 ++ 5 ++ 6 ++ 7 ++++ 8 ++++ 9 +10 + 11 +++ 12 + 13 + 14 + 15 + 16 + 17 +++ 18 ++++ 19 + 20 + 21 + 22 +23 ++ 24 + 25 + 26 + 27 ++ 28 + 29 ++ 30 ++++ 31 +++ 32 ++++ 33 +++ 34++++ 35 ++++ 36 ++++ 37 +++ 38 +++ 39 ++++ 40 ++++ 41 ++++ 42 ++++ 43+++ 44 +++ 45 ++ 46 +++ 47 +++ 48 ++ 49 ++ 50 +++ 51 +++ 52 +++ 53 +++54 ++ 55 +++ 56 + 57 ++ 58 ++ 59 ++ 60 ++ 61 +++ 62 ++ 63 + 64 +++ 65++++ 66 +++ 67 ++++ 68 +++ 69 +++ 70 ++++ 71 +++ 72 +++ 73 +++ 74 ++ 75++++ 76 ++++ 77 ++++ 78 +++ 79 ++++ 80 ++++ 81 ++ 82 ++++ 83 ++++ 84++++ 85 ++ 86 ++++ 87 ++ 88 +++ 89 ++ 90 ++++ 91 ++ 92 +++ 93 + 94 ++ 95++

1. A pharmaceutical composition which comprises a compound selected fromthe group consisting of:12-ethyl-8-{2-[3-(trifluoromethyl)pyridin-2-yl]ethyl}-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,12-ethyl-8-{2-[6-(trifluoromethyl)pyridin-2-yl]ethyl}-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,12-ethyl-8-[2-(3-fluoropyridin-2-yl)ethyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,12-ethyl-8-{2-[4-(trifluoromethyl)pyridin-2-yl]ethyl}-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,8-[2-(3-chloropyridin-2-yl)ethyl]-12-ethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,8-[2-(6-aminopyridin-2-yl)ethyl]-12-ethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one, 12-ethyl-8-phenethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,12-isopropyl-8-phenethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,12-isopropyl-8-[2-(pyridin-2-yl)ethyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one dihydrochloride,12-ethyl-8-[2-(pyridin-2-yl)ethyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,(R)-2,4-dimethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,12-ethyl-8-{2-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,12-ethyl-8-[2-(6-methoxypyridin-2-yl)ethyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,12-ethyl-8-[2-(6-hydroxypyridin-2-yl)ethyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one, 4-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)benzene-1-sulfonamide,4-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)-N-methylbenzene-1-sulfonamide,12-ethyl-8-{2-[3-(trifluoromethoxy)phenyl]ethyl}-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,(R)-4-ethyl-2-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,12-ethyl-8-(3-nitrophenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,12-ethyl-8-(3-methoxyphenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one, tert-butyl(4-(2-(12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl)ethyl)thiazol-2-yl)carbamate,methyl 4-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)benzoate,12-ethyl-8-[2-(pyridin-4-yl)ethyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,12-ethyl-8-[2-(pyridin-3-yl)ethyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,12-ethyl-8-(4-methoxyphenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,12-ethyl-8-(2-methoxyphenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one, 3-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)benzonitrile,4-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)-N,N-dimethylbenzamide,8-[2-fluorophenethyl]-12-methyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,8-[2-fluorophenethyl]-12-isopropyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,(R)-2-isopropyl-4-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-4-ethyl-9-(2-fluorophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-2-ethyl-4-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-9-(3-fluorophenethyl)-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-4-cyclopropyl-9-(2-fluorophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-4-isopropyl-2-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-9-(2-fluorophenethyl)-2,4-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-9-(3-fluorophenethyl)-2,4-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-9-(2-fluorophenethyl)-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-4-cyclopropyl-2-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-4-cyclopropyl-9-(3-fluorophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-4-ethyl-9-(3-fluorophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,8-(3-fluorophenethyl)-12-isopropyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one hydrochloride,(R)-2,4-dimethyl-9-(3-(trifluoromethyl)phenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-2,4-dimethyl-9-(2-(trifluoromethoxy)phenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-9-(2-fluorophenethyl)-2-isopropyl-4-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-9-(3-fluorophenethyl)-2-isopropyl-4-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-2,4-dimethyl-9-(2-(trifluoromethyl)phenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-9-(2,6-difluorophenethyl)-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-9-(2,5-difluorophenethyl)-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-9-(2,3-difluorophenethyl)-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-2-ethyl-9-(2-fluorophenethyl)-4-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-2-ethyl-9-(3-fluorophenethyl)-4-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,2,2,4-trimethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,12-methyl-8-phenethyl-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,8-(3-aminophenethyl)-12-ethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,N-[3-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)phenyl]acetamide,[3-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)phenyl]urea,4-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)-N-methylbenzamide,12-ethyl-8-(2-hydroxyphenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,12-ethyl-8-(3-hydroxyphenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,12-ethyl-8-(4-hydroxyphenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one hydrochloride,8-[2-(2-aminothiazol-4-yl)ethyl]-12-ethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,2,2-diethyl-4-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,4-cyclopropyl-9-(2-fluorophenethyl)-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,8-(2,5-difluorophenethyl)-12-isopropyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,8-(2,3-difluorophenethyl)-12-isopropyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,10-(2-fluorophenethyl)-14-methyl-6-oxa-10,14-diazadispiro[4.1.5.3]pentadecan-15-one,10-(3-fluorophenethyl)-14-methyl-6-oxa-10,14-diazadispiro[4.1.5.3]pentadecan-15-one,(R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,8-(2,5-difluorophenethyl)-12-ethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,12-ethyl-8-(3-fluorophenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,12-ethyl-8-(2-fluorophenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,(R)-9-(2,3-difluorophenethyl)-2,4-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-2,4-diethyl-9-(2-fluorophenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-2,4-diethyl-9-(3-fluorophenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-2-ethyl-9-(3-fluorophenethyl)-4-isopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,4-ethyl-9-(3-fluorophenethyl)-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,4-ethyl-9-(2-fluorophenethyl)-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-2-ethyl-9-(2-fluorophenethyl)-4-isopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-9-(2,5-difluorophenethyl)-2,4-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,9-(3-fluorophenethyl)-4-isopropyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,9-(2-fluorophenethyl)-4-isopropyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,9-(2,3-difluorophenethyl)-4-isopropyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,4-cyclopropyl-9-(2,3-difluorophenethyl)-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,4-cyclopropyl-9-(2,5-difluorophenethyl)-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-9-(2,3-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,9-(2,5-difluorophenethyl)-4-ethyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,9-(2,3-difluorophenethyl)-4-ethyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,9-(2,5-difluorophenethyl)-4-isopropyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-4-cyclopropyl-9-(2,3-difluorophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-4-cyclopropyl-9-(2,5-difluorophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-4-methyl-9-phenethyl-2-(prop-2-yn-1-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-2-(2-hydroxyethyl)-4-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,and(R)-2-benzyl-4-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one;or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, adjuvant or vehicle.
 2. The pharmaceuticalcomposition according to claim 1, wherein the compound is(R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one.3. A method of treating pain in a subject in need thereof, comprisingadministration of an effective amount of a compound selected from thegroup consisting of:12-ethyl-8-{2-[3-(trifluoromethyl)pyridin-2-yl]ethyl}-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,12-ethyl-8-{2-[6-(trifluoromethyl)pyridin-2-yl]ethyl}-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,12-ethyl-8-[2-(3-fluoropyridin-2-yl)ethyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,12-ethyl-8-{2-[4-(trifluoromethyl)pyridin-2-yl]ethyl}-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,8-[2-(3-chloropyridin-2-yl)ethyl]-12-ethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,8-[2-(6-aminopyridin-2-yl)ethyl]-12-ethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one, 12-ethyl-8-phenethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,12-isopropyl-8-phenethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,12-isopropyl-8-[2-(pyridin-2-yl)ethyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one dihydrochloride,12-ethyl-8-[2-(pyridin-2-yl)ethyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,(R)-2,4-dimethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,12-ethyl-8-{2-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,12-ethyl-8-[2-(6-methoxypyridin-2-yl)ethyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,12-ethyl-8-[2-(6-hydroxypyridin-2-yl)ethyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one, 4-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)benzene-1-sulfonamide,4-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)-N-methylbenzene-1-sulfonamide,12-ethyl-8-{2-[3-(trifluoromethoxy)phenyl]ethyl}-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,(R)-4-ethyl-2-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,12-ethyl-8-(3-nitrophenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,12-ethyl-8-(3-methoxyphenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one, tert-butyl(4-(2-(12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl)ethyl)thiazol-2-yl)carbamate,methyl 4-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)benzoate,12-ethyl-8-[2-(pyridin-4-yl)ethyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,12-ethyl-8-[2-(pyridin-3-yl)ethyl]-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,12-ethyl-8-(4-methoxyphenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,12-ethyl-8-(2-methoxyphenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one, 3-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)benzonitrile,4-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)-N,N-dimethylbenzamide,8-[2-fluorophenethyl]-12-methyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,8-[2-fluorophenethyl]-12-isopropyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,(R)-2-isopropyl-4-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-4-ethyl-9-(2-fluorophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-2-ethyl-4-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-9-(3-fluorophenethyl)-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-4-cyclopropyl-9-(2-fluorophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-4-isopropyl-2-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-9-(2-fluorophenethyl)-2,4-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-9-(3-fluorophenethyl)-2,4-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-9-(2-fluorophenethyl)-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-4-cyclopropyl-2-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-4-cyclopropyl-9-(3-fluorophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-4-ethyl-9-(3-fluorophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,8-(3-fluorophenethyl)-12-isopropyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one hydrochloride,(R)-2,4-dimethyl-9-(3-(trifluoromethyl)phenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-2,4-dimethyl-9-(2-(trifluoromethoxy)phenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-9-(2-fluorophenethyl)-2-isopropyl-4-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-9-(3-fluorophenethyl)-2-isopropyl-4-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-2,4-dimethyl-9-(2-(trifluoromethyl)phenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-9-(2,6-difluorophenethyl)-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-9-(2,5-difluorophenethyl)-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-9-(2,3-difluorophenethyl)-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-2-ethyl-9-(2-fluorophenethyl)-4-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-2-ethyl-9-(3-fluorophenethyl)-4-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,2,2,4-trimethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,12-methyl-8-phenethyl-4-oxa-8, 12-diazadispiro[2.1.5.3]tridecan-13-one,8-(3-aminophenethyl)-12-ethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,N-[3-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)phenyl]acetamide,[3-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)phenyl]urea,4-(2-{12-ethyl-13-oxo-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-8-yl}ethyl)-N-methylbenzamide,12-ethyl-8-(2-hydroxyphenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,12-ethyl-8-(3-hydroxyphenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,12-ethyl-8-(4-hydroxyphenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one hydrochloride,8-[2-(2-aminothiazol-4-yl)ethyl]-12-ethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,2,2-diethyl-4-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one4-cyclopropyl-9-(2-fluorophenethyl)-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,8-(2,5-difluorophenethyl)-12-isopropyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,8-(2,3-difluorophenethyl)-12-isopropyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,10-(2-fluorophenethyl)-14-methyl-6-oxa-10,14-diazadispiro[4.1.5.3]pentadecan-15-one,10-(3-fluorophenethyl)-14-methyl-6-oxa-10,14-diazadispiro[4.1.5.3]pentadecan-15-one,(R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,8-(2,5-difluorophenethyl)-12-ethyl-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,12-ethyl-8-(3-fluorophenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,12-ethyl-8-(2-fluorophenethyl)-4-oxa-8,12-diazadispiro[2.1.5.3]tridecan-13-one,(R)-9-(2,3-difluorophenethyl)-2,4-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-2,4-diethyl-9-(2-fluorophenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-2,4-diethyl-9-(3-fluorophenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-2-ethyl-9-(3-fluorophenethyl)-4-isopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,4-ethyl-9-(3-fluorophenethyl)-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,4-ethyl-9-(2-fluorophenethyl)-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-2-ethyl-9-(2-fluorophenethyl)-4-isopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-9-(2,5-difluorophenethyl)-2,4-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,9-(3-fluorophenethyl)-4-isopropyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,9-(2-fluorophenethyl)-4-isopropyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,9-(2,3-difluorophenethyl)-4-isopropyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,4-cyclopropyl-9-(2,3-difluorophenethyl)-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,4-cyclopropyl-9-(2,5-difluorophenethyl)-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-9-(2,3-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,9-(2,5-difluorophenethyl)-4-ethyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,9-(2,3-difluorophenethyl)-4-ethyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,9-(2,5-difluorophenethyl)-4-isopropyl-2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-4-cyclopropyl-9-(2,3-difluorophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-4-cyclopropyl-9-(2,5-difluorophenethyl)-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-4-methyl-9-phenethyl-2-(prop-2-yn-1-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-2-(2-hydroxyethyl)-4-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,(R)-2-benzyl-4-methyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one,and pharmaceutically acceptable salts thereof.
 4. The method accordingto claim 3, wherein the compound is(R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one.5. The method according to claim 3, wherein the pain is selected fromthe group consisting of medium to severe pain, visceral pain, chronicpain, cancer pain, migraine, inflammatory pain, acute pain, neuropathicpain, allodynia, and hyperalgesia.
 6. A process for the preparation of acompound having the structure

which comprises the steps of (a) reacting a compound having thestructure

wherein R₁ is ethyl and R₂ is 2,5-difluorophenethyl, with a compound offormula VI

wherein R₃ is hydrogen, R_(3′) is methyl, and W and LG are leavinggroups, to obtain a compound of formula VII

and carrying out a cyclisation of the resulting compound in a suitablesolvent, in the presence of a strong base and at a temperature comprisedbetween −78° C. and the reflux temperature.